Formulations for oral administration of active agents with controlled absorption profile

ABSTRACT

A pharmaceutical composition comprising a therapeutically active agent and SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) is provided herein. The composition is formulated for oral administration and is such that the SNAC is active in enhancing absorption of the therapeutically active agent for no more than 60 minutes, and/or such that absorption of the therapeutically active agent following oral administration of the composition is characterized by a ratio of AUC to Cmax which is 60 minutes or lower and/or by a Tmax which is 60 minutes or lower. Further disclosed herein are uses and methods utilizing the compositions described herein for treating a condition treatable by oral administration of a therapeutically active agent in a subject in need thereof.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to drugdelivery, and more particularly, but not exclusively, to formulationsand/or systems for oral administration of therapeutically active agents.

Oral administration of peptide and/or protein pharmaceuticals isproblematic due to degradation of peptides and/or proteins in thedigestive system and poor absorption of large molecules.

U.S. Patent Application Publication No. 2007/0087957 describescompositions for oral administration of a protein, the compositionscomprising a protein and an omega-3 fatty acid, as well as the use ofsuch compositions for oral administration of insulin.

Qi & Ping [J Microencapsulation 2004, 21:37-45] describe administrationof enteric microspheres containing insulin with SNAC (sodium8-N-(2-hydroxybenzoyl)aminocaprylate). The enteric microspheres are forprotecting the insulin from digestive enzymes of the stomach and smallintestine, and the SNAC is for enhancing absorption.

U.S. Patent Application Publication No. 2011/0142800 describescompositions for oral administration of a protein, comprising a proteinhaving a molecular weight of up to 100,000 Da, a protease inhibitor, andan absorption enhancer, such as SNAC,N-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD),8-[N-(2-hydroxy-4-methoxybenzoyl)amino]caprylic acid (4-MOAC),8-[N-(2-hydroxy-5-chlorobenzoyl)amino]caprylic acid (5-CNAC) and4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (4-CNAB) and sodiumsalts thereof.

U.S. Pat. No. 8,110,547 describes compositions for buccal administrationof parathyroid hormone (PTH). The composition comprises PTH or afragment or analog thereof, as well as a delivery agent such as 4-MOAC,SNAC, SNAD, 5-CNAC and 4-CNAB.

Parathyroid hormone (PTH) is secreted by the parathyroid gland as apolypeptide containing 84 amino acids. PTH regulates serum calciumlevels by enhancing release of calcium from bones (bone resorption), andby enhancing absorption of calcium in the intestines.

Teriparatide is a recombinant form of the first 34 amino acids of humanPTH (PTH (1-34)), and is used for treatment of osteoporosis.Administration is by subcutaneous injection once per day at a dose of 20μg [Riek & Towler, Mo Med 2011, 108:118-123].

PTH (including PTH (1-34)) has been reported to enhance bone growthprovided that it is administered intermittently, with circulating levelsreturning to control levels within 3 hours [Martin, J Bone Metab 2014,21:8-20]. In contrast, prolonged elevated PTH levels deplete bones byenhancing bone resorption.

Additional background art includes Qi et al. [Acta Pharm Sinica 2004,39:844-848]; International Patent Application Publications WO 00/50386,WO 01/32130, WO 01/32596, WO 03/045306 and WO 2007/121471; JapanesePatent Application Nos. 2005281231 and 2006111558; and U.S. PatentApplication Publication Nos. 2006/0234913 and 2013/0224300.

SUMMARY OF THE INVENTION

According to an aspect of some embodiments of the invention, there isprovided a pharmaceutical composition comprising a therapeuticallyactive agent, and SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate),the composition being formulated such that absorption of thetherapeutically active agent following oral administration of thecomposition is characterized by a ratio of AUC to Cmax which is 60minutes or lower and/or by a Tmax which is 60 minutes or lower.

According to an aspect of some embodiments of the invention, there isprovided a pharmaceutical composition comprising a therapeuticallyactive agent, and SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate),the composition being formulated for oral administration and being suchthat the SNAC is active in enhancing absorption of the therapeuticallyactive agent for no more than 60 minutes.

According to an aspect of some embodiments of the invention, there isprovided a use of a composition described herein in the preparation of amedicament for use in the treatment of a condition treatable by oraladministration of the therapeutically active agent in a subject in needthereof.

According to an aspect of some embodiments of the invention, there isprovided a method of treating a condition treatable by oraladministration of a therapeutically active agent in a subject in needthereof, the method comprising orally administering to the subject acomposition described herein.

According to some embodiments of the invention, the ratio of AUC to Cmaxis 30 minutes or lower.

According to some embodiments of the invention, the Tmax is 30 minutesor lower.

According to some embodiments of the invention, the SNAC is active inenhancing absorption of the therapeutically active agent for no morethan 30 minutes.

According to some embodiments of the invention, the composition furthercomprises at least one protease inhibitor.

According to some embodiments of the invention, the at least oneprotease inhibitor comprises at least one trypsin inhibitor.

According to some embodiments of the invention, the at least one trypsininhibitor is selected from the group consisting of lima bean trypsininhibitor, aprotinin, soybean trypsin inhibitor and ovomucoid trypsininhibitor.

According to some embodiments of the invention, the at least one trypsininhibitor comprises soybean trypsin inhibitor.

According to some embodiments of the invention, the composition furthercomprises a lubricant.

According to some embodiments of the invention, the lubricant ismagnesium stearate.

According to some embodiments of the invention, the composition issoluble in gastric fluid.

According to some embodiments of the invention, the compositiondissolves in gastric fluid in no more than 60 minutes.

According to some embodiments of the invention, the composition isformulated as a tablet.

According to some embodiments of the invention, at least 90 weightpercents of the tablet consists of ingredients selected from the groupconsisting of the therapeutically active agent, SNAC, and at least oneprotease inhibitor.

According to some embodiments of the invention, at least 50 weightpercents of the composition consists of SNAC.

According to some embodiments of the invention, the compositioncomprises at least 50 mg of SNAC.

According to some embodiments of the invention, a bioavailability of thetherapeutically active agent is in a range of from 0.05 to 50%.

According to some embodiments of the invention, a bioavailability of thetherapeutically active agent is in a range of from 0.2 to 5%.

According to some embodiments of the invention, the therapeuticallyactive agent has a molecular weight in a range of 0.5 kDa to 100 kDa.

According to some embodiments of the invention, the therapeuticallyactive agent is a polypeptide.

According to some embodiments of the invention, the polypeptide isselected from the group consisting of parathyroid hormone and a fragmentthereof.

According to some embodiments of the invention, the polypeptidecomprises teriparatide.

According to some embodiments of the invention, an amount of thetherapeutically active agent is in a range of from 100 to 3000 μg.

According to some embodiments of the invention, the composition is foruse in the treatment of a condition treatable by oral administration ofthe therapeutically active agent in a subject in need thereof.

According to some embodiments of the invention, the treatment describedherein comprises enhancing absorption of the therapeutically activeagent for a controlled period of time, such that a ratio of AUC to Cmaxis 60 minutes or lower and/or such that a Tmax is 60 minutes or lower.

According to some embodiments of the invention, the ratio of AUC to Cmaxis 30 minutes or lower.

According to some embodiments of the invention, the treatment comprisesenhancing absorption of the therapeutically active agent for no morethan 60 minutes after the oral administration.

According to some embodiments of the invention, the treatment comprisesenhancing absorption of the therapeutically active agent for no morethan 30 minutes after the oral administration.

According to some embodiments of the invention, the treatment comprisesenhancing absorption of the therapeutically active agent for acontrolled period of time, such that a Tmax upon oral administration isno more than 30 minutes.

According to some embodiments of the invention, the method comprisesenhancing absorption of the therapeutically active agent for acontrolled period of time, such that a ratio of AUC to Cmax is 60minutes or lower and/or such that a Tmax is 60 minutes or lower.

According to some embodiments of the invention, the ratio of AUC to Cmaxis 30 minutes or lower.

According to some embodiments of the invention, the method comprisesenhancing absorption of the therapeutically active agent for no morethan 60 minutes after the oral administration.

According to some embodiments of the invention, the treatment comprisesenhancing absorption of the therapeutically active agent for no morethan 30 minutes after the oral administration.

According to some embodiments of the invention, the method comprisesenhancing absorption of the therapeutically active agent for acontrolled period of time, such that a Tmax upon oral administration isno more than 30 minutes.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings. With specificreference now to the drawings in detail, it is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of embodiments of the invention. In this regard, thedescription taken with the drawings makes apparent to those skilled inthe art how embodiments of the invention may be practiced.

In the drawings:

FIGS. 1A-1C are graphs showing plasma concentrations of parathyroidhormone (1-34) as a function of time after oral administration of atablet according to some embodiments of the invention; each of FIGS.1A-1C present data for a different subject, and each subject wasadministered a tablet on two separate occasions (two weeks apart);

FIG. 2 is a bar graph showing maximal plasma concentrations (Cmax) ofparathyroid hormone (1-34) as a function of time after oraladministration of 200, 400, 680, 1400 or 1800 μg teriparatide accordingto some embodiments of the invention, and after subcutaneousadministration of 20 μg teriparatide;

FIG. 3 is a graph showing plasma concentrations of parathyroid hormone(1-34) as a function of time after oral administration of 1800 μgteriparatide according to some embodiments of the invention, aftersubcutaneous administration of 20 μg teriparatide, or afteradministration of a placebo; and

FIG. 4 is a graph showing plasma concentrations of cAMP as a function oftime after oral administration of 680 μg teriparatide according to someembodiments of the invention, or after subcutaneous administration of 20μg teriparatide.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to drugdelivery, and more particularly, but not exclusively, to formulationsand/or systems for oral administration of therapeutically active agents.

While investigating the enhancement of absorption of therapeuticallyactive agents by SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) uponoral administration, the present inventors have uncovered that certaincompositions comprising SNAC result in pharmacokinetic profilescharacterized by rapid increase in levels of absorbed agent, followedalmost immediately by a rapid decrease in levels of absorbed agent. Theinventors have determined that such pharmacokinetic profiles areassociated with enhancement of absorption by SNAC for a brief period oftime, followed by a decrease in absorption upon rapid inactivation ofthe SNAC due to protonation of SNAC (e.g., conversion of the carboxylatesalt to a carboxylic acid). The present inventors have envisioned thatoral administration of such compositions would be particularly usefulfor treating a variety of conditions in which oral administration hasheretofore been unsuitable, because administration of typical oralformulations is associated with insufficient absorption and/or bygradual absorption over a lengthy period of time.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details set forth in the following description orexemplified by the Examples. The invention is capable of otherembodiments or of being practiced or carried out in various ways.

Referring now to the drawings, FIGS. 1A-1C show that oral administrationof exemplary compositions according to some embodiments of the presentinvention, results in an increase in plasma levels of a polypeptidetherapeutic agent (teriparatide), followed almost immediately by a rapiddecrease in plasma levels of the agent. FIG. 2 shows that the plasmalevels of the agent are proportional to the orally administered dose.FIG. 3 shows that the time during which the orally administered agent isabsorbed into the blood is considerably shorter than when the agent isadministered subcutaneously. FIG. 4 shows that the absorbed agentexhibits a biological effect.

These results indicate that oral administration of compositions asdescribed herein is both an effective and convenient route foradministering a therapeutically active agent, as well as beingassociated with a characteristic pharmacokinetic profile.

According to an aspect of some embodiments of the invention, there isprovided a pharmaceutical composition comprising a therapeuticallyactive agent, and SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

In some embodiments, the composition is formulated such that absorptionof the therapeutically active agent following oral administration of thecomposition is characterized by a ratio of AUC to Cmax which is 60minutes or lower.

In some embodiments, the ratio of AUC to Cmax is 50 minutes or lower.

In some embodiments, the ratio of AUC to Cmax is 40 minutes or lower.

In some embodiments, the ratio of AUC to Cmax is 30 minutes or lower.

In some embodiments, the ratio of AUC to Cmax is 20 minutes or lower.

In some embodiments, the ratio of AUC to Cmax is 15 minutes or lower.

In some embodiments, the ratio of AUC to Cmax is 10 minutes or lower.

As used herein, the phrase “pharmaceutical composition” (also referredto herein, for brevity, as “composition”) refers to a preparation of oneor more therapeutically active agent described herein with otherchemical components such as SNAC, and optionally additional ingredientssuch as described herein. The purpose of a pharmaceutical composition isto facilitate administration of the therapeutically active agent.

Herein the term “therapeutically active agent” refers to the ingredientaccountable for a therapeutic effect, as opposed, for example, toenhancement of absorption of the therapeutically active agent, which iseffected by SNAC.

As used herein the term “AUC” refers to the area under a curve whichrepresents levels of the therapeutically active agent in the blood(e.g., plasma levels) as a function of time following administration,and can be determined by measuring plasma levels of the therapeuticallyactive agent at various time points following administration, asexemplified herein.

As used herein the term “Cmax” refers to the maximal concentration ofthe therapeutically active agent in the blood (e.g., plasma levels), andcan be determined by measuring levels of the therapeutically activeagent at various time points following administration, as exemplifiedherein.

When the therapeutically active agent is present to some degree in theblood prior to administration (e.g., when the therapeutically activeagent is naturally present in the body), the area under the baselinelevels are excluded from the AUC and Cmax (e.g., by subtracting thebaseline level from the measured levels at each time point), such thatthe AUC and Cmax each represent an aspect of the increase above baselinelevels which occurs following administration. The baseline can bedetermined by measuring levels prior to administration and/or bydetermining (e.g., by curve-fitting) the baseline to which levels decayafter administration.

The ratio of AUC to Cmax (i.e., AUC divided by Cmax) will depend on thenature of the pharmacokinetic profile of the composition, particularlyon the shape of the curve which represents levels of the therapeuticallyactive agent in the blood (e.g., plasma levels) as a function of timefollowing administration. Pharmacokinetic profiles characterized by asharp increase and decrease within a brief period of time will tend tohave a relatively low ratio of AUC to Cmax, whereas pharmacokineticprofiles characterized by a more gradual increase and decrease over abroader period of time will tend to have a relatively high ratio of AUCto Cmax.

Without being bound by any particular theory, it is believed that aratio of AUC to Cmax which is 60 minutes or lower, as described herein,is associated with a relatively sharp increase and decrease of levels oftherapeutically active agent in the blood.

The ratio of AUC to Cmax is optionally calculated based on data frommultiple administrations of the composition. In such cases, a ratio ofAUC to Cmax is preferably calculated for each administration, and thenthe ratios calculated for each administration may be averaged.

Without being bound by any particular theory, it is believed thataveraging data (e.g., measured blood levels of a therapeutically activeagent) from different administrations of the therapeutically activeagent will frequently result in a broader curve, and larger ratio of AUCto Cmax, than that which is observed after a single administration.Hence, a ratio of AUC to Cmax calculated for averaged data (as opposedto an average of ratios calculated for each administration, as describedhereinabove) is a less accurate indicator of the effect of thecomposition following administration.

In some embodiments, the composition is formulated for oraladministration and is such that the SNAC is active in enhancingabsorption of the therapeutically active agent for no more than 60minutes. In some embodiments, the SNAC is active in enhancing absorptionof the therapeutically active agent for 50 minutes or lower. In someembodiments, the SNAC is active in enhancing absorption of thetherapeutically active agent for 40 minutes or lower. In someembodiments, the SNAC is active in enhancing absorption of thetherapeutically active agent for 30 minutes or lower. In someembodiments, the SNAC is active in enhancing absorption of thetherapeutically active agent for 20 minutes or lower. In someembodiments, the SNAC is active in enhancing absorption of thetherapeutically active agent for 15 minutes or lower. In someembodiments, the SNAC is active in enhancing absorption of thetherapeutically active agent for 10 minutes or lower.

Herein, the phrase “enhancing absorption” refers to causing an increaseof at least 10% in levels (e.g., plasma levels) of absorbed agent.

The enhancement of absorption by SNAC may be determined, for example, bycomparing a pharmacokinetic profile of the composition with apharmacokinetic profile of an equivalent composition which lacks SNAC(e.g., being identical in all aspects except for the absence of SNAC).The time period during which the composition with SNAC results in anincrease of absorbed therapeutically active agent, in comparison to anequivalent composition without SNAC, is the time during which SNAC isactive in enhancing absorption of the therapeutically active agent. Itis to be appreciated that the time during which SNAC is active inenhancing absorption of the therapeutically active agent (e.g., a timeof 60 minutes or lower, as described herein) does not necessarily beginimmediately upon administration.

In some embodiments, the composition is formulated such that absorptionof the therapeutically active agent following oral administration of thecomposition is characterized by a Tmax of no more than 60 minutes. Insome embodiments, the Tmax is no more than 50 minutes. In someembodiments, the Tmax is no more than 40 minutes. In some embodiments,the Tmax is no more than 30 minutes. In some embodiments, the Tmax is nomore than 25 minutes. In some embodiments, the Tmax is no more than 20minutes. In some embodiments, the Tmax is no more than 15 minutes. Insome embodiments, the Tmax is no more than 10 minutes. In someembodiments, the Tmax is no more than 5 minutes.

As used herein the term “Tmax” refers to the duration of time betweenadministration and when maximal concentration of the therapeuticallyactive agent in the blood (e.g., plasma levels) occurs.

In some embodiments of any of the embodiments described herein, thecomposition is soluble in gastric fluid. In some embodiments, thecomposition dissolves in gastric fluid in no more than 60 minutes. Insome embodiments, the composition dissolves in gastric fluid in no morethan 50 minutes. In some embodiments, the composition dissolves ingastric fluid in no more than 40 minutes. In some embodiments, thecomposition dissolves in gastric fluid in no more than 30 minutes. Insome embodiments, the composition dissolves in gastric fluid in no morethan 20 minutes. In some embodiments, the composition dissolves ingastric fluid in no more than 15 minutes. In some embodiments, thecomposition dissolves in gastric fluid in no more than 10 minutes. Insome embodiments, the composition dissolves in gastric fluid in no morethan 5 minutes.

Herein, the phrases “soluble in gastric fluid”, “dissolves in gastricfluid” and the like refer to solubility in simulated gastric fluidwithout pepsin, at pH 2.0, under conditions according to USP 23Apparatus 2 (paddle) (e.g., 800 ml volume, 50 rotations per minute).Dissolution is indicated by absence of visible composition at the bottomof the fluid. However, visible material suspended in the liquid is notexcluded by the terms “soluble” and “dissolution”. The phrase “solublein gastric fluid” refers herein to dissolution within a period of 6hours.

Without being bound by any particular theory, it is believed thatdissolution, and particularly relatively rapid dissolution, in gastricfluid facilitates rapid absorption of a therapeutically active agent,because both the therapeutically active agent and the SNAC which canenhance absorption of the therapeutically active agent become availablein the stomach soon after oral administration (e.g., prior to passage ofthe composition to the intestines). It is further believed thatdissolution, and particularly relatively rapid dissolution, in gastricfluid facilitates control over the time during which a therapeuticallyactive agent is absorbed, because the SNAC can be inactivated uponexposure to acidic conditions of the stomach due to protonation of SNAC(e.g., conversion of the carboxylate salt to a carboxylic acid), suchthat soon after full dissolution of the composition in the stomach,little or no SNAC remains capable of enhancing absorption of atherapeutically active agent.

In some embodiments of any of the embodiments described herein, thecomposition further comprises at least one protease inhibitor.

Herein throughout, the term “protease inhibitor” refers to a compoundwhich reduces a proteolytic activity of a protease, for example, aproteolytic activity which inactivates a therapeutically active agentdescribed herein. The term “protease inhibitor” encompasses, forexample, both large molecules (e.g., proteins) and small molecules, aswell as both naturally occurring compounds and synthetic compounds.

In some embodiments of any of the embodiments described herein, the atleast one protease inhibitor comprises at least one trypsin inhibitor.In some embodiments, the at least one protease inhibitor consistsessentially of one or more trypsin inhibitor(s).

Examples of trypsin inhibitors which may be utilized in any one of theembodiments described herein include, without limitation, lima beantrypsin inhibitor, aprotinin, soybean trypsin inhibitor, ovomucoidtrypsin inhibitor and any combination thereof. In some embodiments, theat least one trypsin inhibitor comprises soybean trypsin inhibitor(SBTI). In some embodiments, the at least one trypsin inhibitor (anoptionally the at least one protease inhibitor) consists essentially ofSBTI.

In some embodiments of any of the embodiments described herein, the atleast one protease inhibitor comprises at least one serpin. In someembodiments, the at least one protease inhibitor consists essentially ofone or more serpin(s).

Examples of serpins which may be utilized in any one of the embodimentsdescribed herein, include, without limitation, alpha 1-antitrypsin,antitrypsin-related protein, alpha 1-antichymotrypsin, kallistatin,protein C inhibitor, cortisol binding globulin, thyroxine-bindingglobulin, angiotensinogen, centerin, protein Z-related proteaseinhibitor, vaspin, monocyte/neutrophil elastase inhibitor, plasminogenactivator inhibitor-2, squamous cell carcinoma antigen-1 (SCCA-1),squamous cell carcinoma antigen-2 (SCCA-2), maspin, proteinase inhibitor6 (PI-6), megsin, serpin B8 (PI-8), serpin B9 (PI-9), bomapin, yukopin,hurpin/headpin, antithrombin, heparin cofactor II, plasminogen activatorinhibitor 1, glia-derived nexin, pigment epithelium derived factor,alpha 2-antiplasmin, complement 1-inhibitor, 47 kDa heat shock protein(HSP47), neuroserpin and pancpin.

In some embodiments of any of the embodiments described herein, the atleast one protease inhibitor comprises at least one cysteine proteaseinhibitor. In some embodiments, the at least one protease inhibitorconsists essentially of one or more cysteine protease inhibitor(s).

Examples of cysteine protease inhibitors which may be utilized in anyone of the embodiments described herein include, without limitation,type 1 cystatins, type 2 cystatins, human cystatins C, D, S, SN, and SA,cystatin E/M, cystatin F, and type 3 cystatins (including kininogens).

In some embodiments of any of the embodiments described herein, the atleast one protease inhibitor comprises at least one threonine proteaseinhibitor. In some embodiments, the at least one protease inhibitorconsists essentially of one or more threonine protease inhibitor(s).

Examples of threonine protease inhibitors which may be utilized in anyone of the embodiments described herein include, without limitation,bortezomib, MLN-519, ER-807446 and TMC-95A.

In some embodiments of any of the embodiments described herein, the atleast one protease inhibitor comprises at least one aspartic proteaseinhibitor. In some embodiments, the at least one protease inhibitorconsists essentially of one or more aspartic protease inhibitor(s).

Examples of aspartic protease inhibitors which may be utilized in anyone of the embodiments described herein, include, without limitation,α₂-macroglobulin, pepstatin A, aspartic protease inhibitor 11, asparticprotease inhibitor 1, aspartic protease inhibitor 2, aspartic proteaseinhibitor 3, aspartic protease inhibitor 4, aspartic protease inhibitor5, aspartic protease inhibitor 6, aspartic protease inhibitor 7,aspartic protease inhibitor 8, aspartic protease inhibitor 9, pepsininhibitor Dit33, and protease A inhibitor 3.

In some embodiments of any of the embodiments described herein, the atleast one protease inhibitor comprises at least one metalloproteaseinhibitor. In some embodiments, the at least one protease inhibitorconsists essentially of one or more metalloprotease inhibitor(s).

Examples of metalloprotease inhibitors which may be utilized in any oneof the embodiments described herein, include, without limitation,angiotensin-1-converting enzyme inhibitory peptide, antihemorrhagicfactor BJ46a, beta-casein, proteinase inhibitor CeKI, venommetalloproteinase inhibitor DM43, carboxypeptidase A inhibitor, smpI,IMPI, alkaline proteinase, latexin, carboxypeptidase inhibitor,antihemorrhagic factor HSF, testican-3, SPOCK3, TIMP1, metalloproteinaseinhibitor 1, metalloproteinase inhibitor 2, TIMP2, metalloproteinaseinhibitor 3, TIMP3, metalloproteinase inhibitor 4, TIMP4, putativemetalloproteinase inhibitor tag-225, tissue inhibitor ofmetalloprotease, WAP, kazal inhibitor, immunoglobulin, and kunitz andNTR domain-containing protein 1.

Examples of protease inhibitors which may be utilized in any one of theembodiments described herein also include, without limitation,AEBSF-HCl, ε-aminocaproic acid, α1-antichymotypsin, antipain,antithrombin III, α1-antitrypsin, APMSF (4-amidinophenyl-methanesulfonyl-fluoride), sprotinin, benzamidine, chymostatin, DFP(diisopropylfluoro-phosphate), leupeptin,4-(2-Aminoethyl)-benzenesulfonyl fluoride hydrochloride, PMSF(phenylmethyl sulfonyl fluoride), TLCK(1-chloro-3-tosylamido-7-amino-2-heptanone), TPCK(1-chloro-3-tosylamido-4-phenyl-2-butanone), pentamidine isothionate,pepstatin, guanidium, α2-macroglobulin, a chelating agent of zinc, andiodoacetate.

In some embodiments of any one of the embodiments described herein, theamount of a protease inhibitor in a unit dosage form described herein isat least about 0.1 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 0.2mg. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 0.3 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 0.4 mg. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 0.6 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 0.8mg. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 1 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 1.5 mg. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 2 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 2.5mg. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 3 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 5 mg. In some embodiments, the amountof a protease inhibitor in a unit dosage form described herein is atleast about 7 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 10mg. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 12 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 15 mg. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 20 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 30mg. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 50 mg. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 70 mg. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 100 mg.

In some embodiments of any one of the embodiments described herein, theamount of a protease inhibitor in a unit dosage form described herein isin a range of from 0.1 to 1 mg. In some embodiments, the amount of aprotease inhibitor in a unit dosage form described herein is in a rangeof from 0.2 to 1 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is in a range of from0.3 to 1 mg. In some embodiments, the amount of a protease inhibitor ina unit dosage form described herein is in a range of from 0.5 to 1 mg.

In some embodiments of any one of the embodiments described herein, theamount of a protease inhibitor in a unit dosage form described herein isin a range of from 0.1 to 2 mg. In some embodiments, the amount of aprotease inhibitor in a unit dosage form described herein is in a rangeof from 0.2 to 2 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is in a range of from0.3 to 2 mg. In some embodiments, the amount of a protease inhibitor ina unit dosage form described herein is in a range of from 0.5 to 2 mg.In some embodiments, the amount of a protease inhibitor in a unit dosageform described herein is in a range of from 1 to 2 mg.

In some embodiments of any one of the embodiments described herein, theamount of a protease inhibitor in a unit dosage form described herein isin a range of from 1 to 10 mg. In some embodiments, the amount of aprotease inhibitor in a unit dosage form described herein is in a rangeof from 2 to 10 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is in a range of from 3to 10 mg. In some embodiments, the amount of a protease inhibitor in aunit dosage form described herein is in a range of from 5 to 10 mg.

In some embodiments of any one of the embodiments described herein, theamount of a protease inhibitor in a unit dosage form described herein isin a range of from 1 to 20 mg. In some embodiments, the amount of aprotease inhibitor in a unit dosage form described herein is in a rangeof from 2 to 20 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is in a range of from 3to 20 mg. In some embodiments, the amount of a protease inhibitor in aunit dosage form described herein is in a range of from 5 to 20 mg. Insome embodiments, the amount of a protease inhibitor in a unit dosageform described herein is in a range of from 10 to 20 mg.

In some embodiments of any one of the embodiments described herein, theamount of a protease inhibitor in a unit dosage form described herein isin a range of from 10 to 100 mg. In some embodiments, the amount of aprotease inhibitor in a unit dosage form described herein is in a rangeof from 20 to 100 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is in a range of from30 to 100 mg. In some embodiments, the amount of a protease inhibitor ina unit dosage form described herein is in a range of from 50 to 100 mg.

In some embodiments of any one of the embodiments described herein, theamount of a protease inhibitor in a unit dosage form described herein isin a range of from 10 to 200 mg. In some embodiments, the amount of aprotease inhibitor in a unit dosage form described herein is in a rangeof from 20 to 200 mg. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is in a range of from30 to 200 mg. In some embodiments, the amount of a protease inhibitor ina unit dosage form described herein is in a range of from 50 to 200 mg.In some embodiments, the amount of a protease inhibitor in a unit dosageform described herein is in a range of from 100 to 200 mg.

In some embodiments of any one of the embodiments described herein, theamount of a protease inhibitor in a unit dosage form described herein isat least about 10 kallikrein inactivator units (k.i.u.). In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 12 k.i.u. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 15 k.i.u. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 20k.i.u. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 30 k.i.u. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 40 k.i.u. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 50 k.i.u. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 70k.i.u. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 100 k.i.u. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 150 k.i.u. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 200 k.i.u. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 300k.i.u. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 500 k.i.u. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 700 k.i.u. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 1000 k.i.u. In some embodiments, the amount of a proteaseinhibitor in a unit dosage form described herein is at least about 1500k.i.u. In some embodiments, the amount of a protease inhibitor in a unitdosage form described herein is at least about 3000 k.i.u. In someembodiments, the amount of a protease inhibitor in a unit dosage formdescribed herein is at least about 4000 k.i.u. In some embodiments, theamount of a protease inhibitor in a unit dosage form described herein isat least about 5000 k.i.u.

Herein and in the art, a “kallikrein inactivating unit” (k.i.u) refersto an amount of protease inhibitor that has the ability to inhibit 2units of kallikrein by 50% (e.g., in aqueous solution at an optimal pHand solution volume for activity of the protease inhibitor).

In some embodiments of any one of the embodiments described herein, aweight ratio of protease inhibitor to therapeutically active agent is ina range of from 1:1 to 5:1 (protease inhibitor: therapeutically activeagent). In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 5:1 to 10:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 10:1 to 20:1. In some embodiments, aweight ratio of protease inhibitor to therapeutically active agent is ina range of from 20:1 to 30:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1. In some embodiments, a weight ratio of protease inhibitorto therapeutically active agent is in a range of from 40:1 to 50:1. Insome embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 50:1 to 75:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1. In some embodiments, aweight ratio of protease inhibitor to therapeutically active agent is ina range of from 100:1 to 200:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from200:1 to 300:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 300:1 to400:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 400:1 to 500:1. Insome embodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, theSNAC may optionally be replaced with a similar compound, such as SNAD(sodium 10-N-(2-hydroxybenzoyl)aminodecanoic acid). As shown below, thestructure of SNAD differs from that of SNAC only in the length of thefatty acid moiety.

In some embodiments of any one of the embodiments described herein, theSNAC may optionally be replaced with a similar compound, wherein thecaprylic acid moiety of SNAC is replaced by another fatty acid moiety atleast 6 carbon atoms in length, for example, from 6 to 20 carbon atomsin length, optionally from 6 to 18 carbon atoms in length, optionallyfrom 6 to 16 carbon atoms in length, optionally from 6 to 14 carbonatoms in length, optionally from 6 to 12 carbon atoms in length andoptionally from 6 to 10 carbon atoms in length. The fatty acid moietymay be saturated (e.g., as are caprylic acid in SNAC and decanoic acidin SNAD) or unsaturated (i.e., comprising at least one unsaturatedcarbon-carbon bond).

In some embodiments of any one of the embodiments described herein, aconcentration of SNAC in a composition described herein is in a range offrom 2.5 to 99.4 weight percents. In some of the aforementionedembodiments, the concentration of SNAC is in a range of from 2.5 to 10weight percents. In some of the aforementioned embodiments, theconcentration of SNAC is in a range of from 8 to 15 weight percents. Insome of the aforementioned embodiments, the concentration of SNAC is ina range of from 10 to 20 weight percents. In some of the aforementionedembodiments, the concentration of SNAC is in a range of from 15 to 30weight percents. In some of the aforementioned embodiments, theconcentration of SNAC is in a range of from 20 to 40 weight percents. Insome of the aforementioned embodiments, the concentration of SNAC is ina range of from 30 to 50 weight percents. In some of the aforementionedembodiments, the concentration of SNAC is in a range of from 40 to 60weight percents. In some of the aforementioned embodiments, theconcentration of SNAC is in a range of from 50 to 70 weight percents. Insome of the aforementioned embodiments, the concentration of SNAC is ina range of from 2.5 to 10 weight percents. In some of the aforementionedembodiments, the concentration of SNAC is in a range of from 2.5 to 10weight percents. In some of the aforementioned embodiments, theconcentration of SNAC is in a range of from 70 to 99.4 weight percents.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to the therapeutically active agent is in a rangeof from 5:1 to 10:1 (SNAC: therapeutically active agent). In someembodiments, the ratio is about 7.5:1. In some embodiments, thecomposition further comprises a protease inhibitor. In some of theaforementioned embodiments wherein the composition comprises a proteaseinhibitor, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 1:1 to 5:1 (protease inhibitor:therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent is in a range offrom 10:1 to 20:1 (SNAC: therapeutically active agent). In someembodiments, the ratio is about 15:1. In some embodiments, thecomposition further comprises a protease inhibitor. In some of theaforementioned embodiments wherein the composition comprises a proteaseinhibitor, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 1:1 to 5:1 (protease inhibitor:therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent is in a range offrom 20:1 to 30:1 (SNAC: therapeutically active agent). In someembodiments, the ratio is about 25:1. In some embodiments, thecomposition further comprises a protease inhibitor. In some of theaforementioned embodiments wherein the composition comprises a proteaseinhibitor, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 1:1 to 5:1 (protease inhibitor:therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent is in a range offrom 30:1 to 50:1 (SNAC: therapeutically active agent). In someembodiments, the ratio is about 40:1. In some embodiments, thecomposition further comprises a protease inhibitor. In some of theaforementioned embodiments wherein the composition comprises a proteaseinhibitor, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 1:1 to 5:1 (protease inhibitor:therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent is in a range offrom 50:1 to 100:1 (SNAC: therapeutically active agent). In someembodiments, the ratio is about 75:1. In some embodiments, thecomposition further comprises a protease inhibitor. In some of theaforementioned embodiments wherein the composition comprises a proteaseinhibitor, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 1:1 to 5:1 (protease inhibitor:therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent is in a range offrom 100:1 to 200:1 (SNAC: therapeutically active agent). In someembodiments, the ratio is about 150:1. In some embodiments, thecomposition further comprises a protease inhibitor. In some of theaforementioned embodiments wherein the composition comprises a proteaseinhibitor, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 1:1 to 5:1 (protease inhibitor:therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent is in a range offrom 200:1 to 300:1 (SNAC: therapeutically active agent). In someembodiments, the ratio is about 250:1. In some embodiments, thecomposition further comprises a protease inhibitor. In some of theaforementioned embodiments wherein the composition comprises a proteaseinhibitor, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 1:1 to 5:1 (protease inhibitor:therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent is in a range offrom 300:1 to 500:1 (SNAC: therapeutically active agent). In someembodiments, the ratio is about 400:1. In some embodiments, thecomposition further comprises a protease inhibitor. In some of theaforementioned embodiments wherein the composition comprises a proteaseinhibitor, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 1:1 to 5:1 (protease inhibitor:therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, aweight ratio of SNAC to therapeutically active agent is in a range offrom 500:1 to 1000:1 (SNAC: therapeutically active agent). In someembodiments, the ratio is about 750:1. In some embodiments, thecomposition further comprises a protease inhibitor. In some of theaforementioned embodiments wherein the composition comprises a proteaseinhibitor, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 1:1 to 5:1 (protease inhibitor:therapeutically active agent), optionally about 3:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 5:1 to 10:1, optionally about 7.5:1.In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 10:1 to 20:1,optionally about 15:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 20:1 to30:1, optionally about 25:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from30:1 to 40:1, optionally about 35:1. In some embodiments, a weight ratioof protease inhibitor to therapeutically active agent is in a range offrom 40:1 to 50:1, optionally about 45:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 50:1 to 75:1, optionally about 62.5:1. In someembodiments, a weight ratio of protease inhibitor to therapeuticallyactive agent is in a range of from 75:1 to 100:1, optionally about87.5:1. In some embodiments, a weight ratio of protease inhibitor totherapeutically active agent is in a range of from 100:1 to 200:1,optionally about 150:1. In some embodiments, a weight ratio of proteaseinhibitor to therapeutically active agent is in a range of from 200:1 to300:1, optionally about 250:1. In some embodiments, a weight ratio ofprotease inhibitor to therapeutically active agent is in a range of from300:1 to 400:1, optionally about 350:1. In some embodiments, a weightratio of protease inhibitor to therapeutically active agent is in arange of from 400:1 to 500:1, optionally about 450:1. In someembodiments, the protease inhibitor is soybean trypsin inhibitor.

In some embodiments of any one of the embodiments described herein, theamount of SNAC in a unit dosage form described herein is at least about0.1 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is at least about 0.2 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is at least about0.3 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is at least about 0.4 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is at least about0.6 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is at least about 0.8 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is at least about1 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is at least about 1.5 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is at least about2 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is at least about 2.5 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is at least about3 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is at least about 5 mg. In some embodiments, the amountof SNAC in a unit dosage form described herein is at least about 7 mg.In some embodiments, the amount of SNAC in a unit dosage form describedherein is at least about 10 mg. In some embodiments, the amount of SNACin a unit dosage form described herein is at least about 12 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis at least about 15 mg. In some embodiments, the amount of SNAC in aunit dosage form described herein is at least about 20 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis at least about 30 mg. In some embodiments, the amount of SNAC in aunit dosage form described herein is at least about 50 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis at least about 70 mg. In some embodiments, the amount of SNAC in aunit dosage form described herein is at least about 100 mg. In someembodiments, the amount of therapeutically active agent is in accordancewith any one of the ratios of SNAC to therapeutically active agentdescribed herein. In some embodiments, the composition further comprisesat least one protease inhibitor in an amount which is in accordance withany one of the ratios of protease inhibitor to therapeutically activeagent described herein.

In some embodiments of any one of the embodiments described herein, theamount of SNAC in a unit dosage form described herein is in a range offrom 0.1 to 1 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 0.2 to 1 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 0.3 to 1 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 0.5 to1 mg.

In some embodiments of any one of the embodiments described herein, theamount of SNAC in a unit dosage form described herein is in a range offrom 0.1 to 2 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 0.2 to 2 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 0.3 to 2 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 0.5 to2 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 1 to 2 mg.

In some embodiments of any one of the embodiments described herein, theamount of SNAC in a unit dosage form described herein is in a range offrom 1 to 10 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 2 to 10 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 3 to 10 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 5 to10 mg.

In some embodiments of any one of the embodiments described herein, theamount of SNAC in a unit dosage form described herein is in a range offrom 1 to 20 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 2 to 20 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 3 to 20 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 5 to20 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 10 to 20 mg.

In some embodiments of any one of the embodiments described herein, theamount of SNAC in a unit dosage form described herein is in a range offrom 10 to 100 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 20 to 100 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 30 to 100 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 50 to100 mg.

In some embodiments of any one of the embodiments described herein, theamount of SNAC in a unit dosage form described herein is in a range offrom 10 to 200 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 20 to 200 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 30 to 200 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 50 to200 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 100 to 200 mg.

In some embodiments of any one of the embodiments described herein, theamount of SNAC in a unit dosage form described herein is in a range offrom 10 to 500 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 20 to 500 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 30 to 500 mg. In some embodiments, the amount ofSNAC in a unit dosage form described herein is in a range of from 50 to500 mg. In some embodiments, the amount of SNAC in a unit dosage formdescribed herein is in a range of from 100 to 500 mg. In someembodiments, the amount of SNAC in a unit dosage form described hereinis in a range of from 200 to 500 mg.

In some embodiments of any one of the embodiments described herein, theamount of SNAC in a unit dosage form described herein is in a range offrom 10 to 1000 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 20 to 1000 mg. Insome embodiments, the amount of SNAC in a unit dosage form describedherein is in a range of from 30 to 1000 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is in a range offrom 50 to 1000 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 100 to 1000 mg. Insome embodiments, the amount of SNAC in a unit dosage form describedherein is in a range of from 200 to 1000 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is in a range offrom 500 to 1000 mg.

In some embodiments of any one of the embodiments described herein, theamount of SNAC in a unit dosage form described herein is in a range offrom 10 to 1000 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 20 to 1000 mg. Insome embodiments, the amount of SNAC in a unit dosage form describedherein is in a range of from 30 to 1000 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is in a range offrom 50 to 1000 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 100 to 1000 mg. Insome embodiments, the amount of SNAC in a unit dosage form describedherein is in a range of from 200 to 1000 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is in a range offrom 500 to 1000 mg.

In some embodiments of any one of the embodiments described herein, theamount of SNAC in a unit dosage form described herein is in a range offrom 10 to 2000 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 20 to 2000 mg. Insome embodiments, the amount of SNAC in a unit dosage form describedherein is in a range of from 30 to 2000 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is in a range offrom 50 to 2000 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 100 to 2000 mg. Insome embodiments, the amount of SNAC in a unit dosage form describedherein is in a range of from 200 to 2000 mg. In some embodiments, theamount of SNAC in a unit dosage form described herein is in a range offrom 500 to 2000 mg. In some embodiments, the amount of SNAC in a unitdosage form described herein is in a range of from 1000 to 2000 mg.

In some embodiments of any one of the embodiments described herein, aunit dosage form described herein comprises at least 50 μg oftherapeutically active agent. In some embodiments, the compositioncomprises at least 100 μg of therapeutically active agent. In someembodiments, the composition comprises at least 200 μg oftherapeutically active agent. In some embodiments, the compositioncomprises at least 500 μg of therapeutically active agent. In someembodiments, the amount of SNAC is in accordance with any one of theratios of SNAC to therapeutically active agent described herein. In someembodiments, the composition further comprises at least one proteaseinhibitor in an amount which is in accordance with any one of the ratiosof protease inhibitor to therapeutically active agent described herein.

In some embodiments of any one of the embodiments described herein, aunit dosage form described herein comprises 500 mg or less oftherapeutically active agent. In some embodiments, the unit dosage formcomprises 200 mg or less of therapeutically active agent. In someembodiments, the unit dosage form comprises 100 mg or less oftherapeutically active agent. In some embodiments, the unit dosage formcomprises 50 mg or less of therapeutically active agent. In someembodiments, the unit dosage form comprises 20 mg or less oftherapeutically active agent. In some embodiments, the unit dosage formcomprises 10 mg or less of therapeutically active agent. In someembodiments, the unit dosage form comprises 5 mg or less oftherapeutically active agent. In some embodiments, the unit dosage formcomprises 3 mg (3000μ.g) or less of therapeutically active agent. Insome embodiments, the unit dosage form comprises 2000 μg or less oftherapeutically active agent. In some embodiments, the unit dosage formcomprises 1000 μg or less of therapeutically active agent. In someembodiments, the amount of SNAC is in accordance with any one of theratios of SNAC to therapeutically active agent described herein. In someembodiments, the composition further comprises at least one proteaseinhibitor in an amount which is in accordance with any one of the ratiosof protease inhibitor to therapeutically active agent described herein.

In some embodiments of any one of the embodiments described herein, theunit dosage form comprises from 100 μg to 500 mg of therapeuticallyactive agent. In some embodiments, the unit dosage form comprises 100 μgto 200 mg of therapeutically active agent. In some embodiments, the unitdosage form comprises 100 μg to 100 mg of therapeutically active agent.In some embodiments, the unit dosage form comprises 100 μg to 50 mg oftherapeutically active agent. In some embodiments, the unit dosage formcomprises 100 μg to 20 mg of therapeutically active agent. In someembodiments, the unit dosage form comprises 100 μg to 10 mg oftherapeutically active agent. In some embodiments, the unit dosage formcomprises 100 μg to 5 mg of therapeutically active agent. In someembodiments, the unit dosage form comprises from 100 to 3000 μg oftherapeutically active agent. In some embodiments, the unit dosage formcomprises from 100 to 2000 μg of therapeutically active agent. In someembodiments, the unit dosage form comprises about 750 μg oftherapeutically active agent. In some embodiments, the amount of SNAC isin accordance with any one of the ratios of SNAC to therapeuticallyactive agent described herein. In some embodiments, the compositionfurther comprises at least one protease inhibitor in an amount which isin accordance with any one of the ratios of protease inhibitor totherapeutically active agent described herein.

In some embodiments of any one of the embodiments described herein, theunit dosage form comprises from 200 μg to 500 mg of therapeuticallyactive agent. In some embodiments, the unit dosage form comprises 200 μgto 200 mg of therapeutically active agent. In some embodiments, the unitdosage form comprises 200 μg to 100 mg of therapeutically active agent.In some embodiments, the unit dosage form comprises 200 μg to 50 mg oftherapeutically active agent. In some embodiments, the unit dosage formcomprises 200 μg to 20 mg of therapeutically active agent. In someembodiments, the unit dosage form comprises 200 μg to 10 mg oftherapeutically active agent. In some embodiments, the unit dosage formcomprises 200 μg to 5 mg of therapeutically active agent. In someembodiments, the unit dosage form comprises from 200 to 3000 μg oftherapeutically active agent. In some embodiments, the unit dosage formcomprises from 200 to 2000 μg of therapeutically active agent. In someembodiments, the unit dosage form comprises from 500 to 1000 μg oftherapeutically active agent. In some embodiments, the therapeuticallyactive agent is a parathyroid hormone or a fragment thereof. In someembodiments, the therapeutically active agent is teriparatide. In someembodiments, the amount of SNAC is in accordance with any one of theratios of SNAC to therapeutically active agent described herein. In someembodiments, the composition further comprises at least one proteaseinhibitor in an amount which is in accordance with any one of the ratiosof protease inhibitor to therapeutically active agent described herein.

Compositions described herein are particularly suitable for controllingthe absorption of therapeutically active agents whose absorption uponoral administration is limited, as absorption of such therapeuticallyactive agents is particularly dependent on absorption enhancementactivity of SNAC. Limited absorption of a therapeutically active agentmay be, for example, due to a large molecular weight, stronghydrophilicity (e.g., which inhibits crossing of lipid membranes in thegastrointestinal tract), strong lipophilicity (e.g., which reducesdissolution and consequently diffusion in the gastrointestinal tract,inhibits permeation of hydrophilic layers such as intestinal mucuslinings, and/or results in accumulation in lipid membranes), and/ordegradation in the gastrointestinal tract (e.g., by proteolysis).

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 0.5 kDa.In some embodiments, the molecular weight is in a range of from 0.5 to150 kDa. In some embodiments, the molecular weight is in a range of from0.5 to 100 kDa. In some embodiments, the molecular weight is in a rangeof from 0.5 to 75 kDa. In some embodiments, the molecular weight is in arange of from 0.5 to 50 kDa. In some embodiments, the molecular weightis in a range of from 0.5 to 30 kDa. In some embodiments, the molecularweight is in a range of from 0.5 to 20 kDa. In some embodiments, themolecular weight is in a range of from 0.5 to 10 kDa. In someembodiments, the molecular weight is in a range of from 0.5 to 7.5 kDa.In some embodiments, the molecular weight is in a range of from 0.5 to 5kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 1 kDa.In some embodiments, the molecular weight is in a range of from 1 to 150kDa. In some embodiments, the molecular weight is in a range of from 1to 100 kDa. In some embodiments, the molecular weight is in a range offrom 1 to 75 kDa. In some embodiments, the molecular weight is in arange of from 1 to 50 kDa. In some embodiments, the molecular weight isin a range of from 1 to 30 kDa. In some embodiments, the molecularweight is in a range of from 1 to 20 kDa. In some embodiments, themolecular weight is in a range of from 1 to 10 kDa. In some embodiments,the molecular weight is in a range of from 1 to 7.5 kDa. In someembodiments, the molecular weight is in a range of from 1 to 5 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 2 kDa.In some embodiments, the molecular weight is in a range of from 2 to 150kDa. In some embodiments, the molecular weight is in a range of from 2to 100 kDa. In some embodiments, the molecular weight is in a range offrom 2 to 75 kDa. In some embodiments, the molecular weight is in arange of from 2 to 50 kDa. In some embodiments, the molecular weight isin a range of from 2 to 30 kDa. In some embodiments, the molecularweight is in a range of from 2 to 20 kDa. In some embodiments, themolecular weight is in a range of from 2 to 10 kDa. In some embodiments,the molecular weight is in a range of from 2 to 7.5 kDa. In someembodiments, the molecular weight is in a range of from 2 to 5 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 3 kDa.In some embodiments, the molecular weight is in a range of from 3 to 150kDa. In some embodiments, the molecular weight is in a range of from 3to 100 kDa. In some embodiments, the molecular weight is in a range offrom 3 to 75 kDa. In some embodiments, the molecular weight is in arange of from 3 to 50 kDa. In some embodiments, the molecular weight isin a range of from 3 to 30 kDa. In some embodiments, the molecularweight is in a range of from 3 to 20 kDa. In some embodiments, themolecular weight is in a range of from 3 to 10 kDa. In some embodiments,the molecular weight is in a range of from 3 to 7.5 kDa. In someembodiments, the molecular weight is in a range of from 3 to 5 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 4 kDa.In some embodiments, the molecular weight is in a range of from 4 to 150kDa. In some embodiments, the molecular weight is in a range of from 4to 100 kDa. In some embodiments, the molecular weight is in a range offrom 4 to 75 kDa. In some embodiments, the molecular weight is in arange of from 4 to 50 kDa. In some embodiments, the molecular weight isin a range of from 4 to 30 kDa. In some embodiments, the molecularweight is in a range of from 4 to 20 kDa. In some embodiments, themolecular weight is in a range of from 4 to 10 kDa. In some embodiments,the molecular weight is in a range of from 4 to 7.5 kDa. In someembodiments, the molecular weight is in a range of from 4 to 5 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 5 kDa.In some embodiments, the molecular weight is in a range of from 5 to 150kDa. In some embodiments, the molecular weight is in a range of from 5to 100 kDa. In some embodiments, the molecular weight is in a range offrom 5 to 75 kDa. In some embodiments, the molecular weight is in arange of from 5 to 50 kDa. In some embodiments, the molecular weight isin a range of from 5 to 30 kDa. In some embodiments, the molecularweight is in a range of from 5 to 20 kDa. In some embodiments, themolecular weight is in a range of from 5 to 10 kDa. In some embodiments,the molecular weight is in a range of from 5 to 7.5 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 10 kDa.In some embodiments, the molecular weight is in a range of from 10 to150 kDa. In some embodiments, the molecular weight is in a range of from10 to 100 kDa. In some embodiments, the molecular weight is in a rangeof from 10 to 75 kDa. In some embodiments, the molecular weight is in arange of from 10 to 50 kDa. In some embodiments, the molecular weight isin a range of from 10 to 30 kDa. In some embodiments, the molecularweight is in a range of from 10 to 20 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 20 kDa.In some embodiments, the molecular weight is in a range of from 20 to150 kDa. In some embodiments, the molecular weight is in a range of from20 to 100 kDa. In some embodiments, the molecular weight is in a rangeof from 20 to 75 kDa. In some embodiments, the molecular weight is in arange of from 20 to 50 kDa. In some embodiments, the molecular weight isin a range of from 20 to 30 kDa.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 50 kDa.In some embodiments, the molecular weight is in a range of from 50 to150 kDa. In some embodiments, the molecular weight is in a range of from50 to 100 kDa. In some embodiments, the molecular weight is in a rangeof from 50 to 75 kDa.

Without being bound by any particular theory, it is believed that agentshaving a relatively high molecular weight (e.g., at least 0.5 kDa, atleast 1 kDa, at least 2 kDa, at least 3 kDa, at least 4 kDa) tend to beless efficiently absorbed upon oral administration than relatively smallmolecules (e.g., molecules having a molecular weight of less than 0.5kDa, or less than 1 kDa) and therefore, their absorption is particularlysusceptible to enhancement by SNAC activity.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is a hormone and/or cytokine (e.g., ahormone).

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is a polypeptide. In some embodiments, thepolypeptide is a polypeptide hormone and/or cytokine, or a fragmentthereof (e.g., a fragment exhibiting an activity of the hormone and/orcytokine), or a homolog of a polypeptide hormone and/or cytokine orfragment thereof.

Examples of polypeptides which may be utilized (per se or as fragmentsthereof and/or homologs thereof) as therapeutically active agentsaccording to embodiments of the invention include, without limitation,insulin, a glucagon, a parathyroid hormone, an interferon, a growthhormone, an erythropoietin, a calcitonin, an omentin, a motilin, aleptin, a peptide YY, a GLP-1 (glucagon-like peptide-1), a GLP-2(glucagon-like peptide-2), granulocyte-colony stimulating factor(G-CSF), an antibody (e.g., monoclonal antibody), an interleukin, anerythropoietin, a vasopressin, a vasoactive intestinal peptide, apituitary adenylate cyclase-activating peptide (PACAP), a blood clottingfactor, an endomorphin (e.g., endomorphin-1, endomorphin-2), a TNFinhibitor (e.g., infliximab, adalimumab, certolizumab, golimumab,etanercept), disitertide, octreotide (a somatotropin analog),davunetide, icatibant, glucocerebrosidase, a gonadotropin releasinghormone (GnRH), acyline (a GnRH antagonist), and a GLP-1 agonist such asexendin-4 (including exenatide and lixisenatide). Examples of growthhormones, include, without limitation, somatotropin (growth hormone 1),growth hormone 2, and growth factors (e.g., insulin-like growth factor 1(IGF-1), fibroblast growth factor (FGF), ciliary neurotrophic factor).

Insulin, glucagon, parathyroid hormone, erythropoietin, calcitonin,motilin, leptin, peptide YY, GLP-1 (including derivatives thereof suchas liraglutide, taspoglutide, albiglutide and dulaglutide), GLP-2, GnRH(including derivatives thereof such as leuprorelin, buserelin,histrelin, goserelin, deslorelin, nafarelin and triptorelin),vasopressin (including derivatives thereof such as desmopressin),vasoactive intestinal peptide (including aviptadil), pituitary adenylatecyclase-activating peptide (PACAP), growth hormones (including axokine,a homolog of a fragment of ciliary neurotrophic factor) and G-CSF arenon-limiting examples of polypeptide hormones.

Interferons, interleukins, erythropoietin and analogs thereof (e.g.,darbepoetin), omentin and G-CSF are non-limiting examples of polypeptidecytokines.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is parathyroid hormone (PTH) or a fragmentthereof (e.g., a fragment exhibiting an activity of PTH). In someembodiments, the polypeptide is teriparatide (i.e., a PTH fragmenthaving amino acid residues 1-34 of PTH).

Herein, the term “parathyroid hormone” or its abbreviation “PTH”encompasses parathyroid hormone (having a naturally occurring amino acidsequence, e.g., in humans) and homologs of the parathyroid hormone. A“fragment” of parathyroid hormone encompasses fragments of parathyroidhormone having a naturally occurring amino acid sequence (e.g., inhumans) and homologs of such fragments.

Without being bound by any particular theory, it is believed that agentswhich are polypeptides tend to be poorly absorbed upon oraladministration, for example, due to their polarity and/or relativelylarge molecular weight; and therefore, their absorption is particularlysusceptible to enhancement by SNAC activity.

In some embodiments of any one of the embodiments described hereinwherein the therapeutically active agents is a polypeptide, thecomposition further comprises at least one protease inhibitor, forexample, according to any one of the embodiments described hereinrelating to a protease inhibitor.

It has been reported that therapeutically active agents which exhibitmore than one of the following criteria tend to be poorly absorbed uponoral administration (when administered alone), a phenomenon referred toin the art as “Lipinski's rule of 5”:

-   -   (i) a total number of nitrogen-hydrogen bonds and oxygen        hydrogen bonds (which are typically hydrogen bond donors) which        is more than 5;    -   (ii) a total number of nitrogen and oxygen atoms (which are        typically hydrogen bond acceptors) which is more than 5;    -   (iii) an octanol-water partition coefficient (log P) which is        greater than 5; and/or    -   (iv) a molecular weight of at least 500 Da (0.5 kDa).

The abovementioned criteria (i) and (ii) are associated with hydrogenbonding and hydrophilicity; whereas criteria (iii) is associated withlipophilicity.

As described herein, therapeutically active agents poorly absorbed uponoral administration when administered alone are particularly suitablefor being included in compositions described herein, in order to enhancetheir absorption.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent meets at least one of the abovementionedcriteria (i), (ii), (iii) and (iv). In some embodiments, thetherapeutically active agent meets at least two of the abovementionedcriteria (i), (ii), (iii) and (iv). In some embodiments, thetherapeutically active agent meets at least three of the abovementionedcriteria (i), (ii), (iii) and (iv). In some embodiments, thetherapeutically active agent meets all four of the abovementionedcriteria (i), (ii), (iii) and (iv).

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of at least 0.5 kDa,in accordance with any one of the embodiments described herein relatingto a molecular weight of at least 0.5 kDa, and further meets at leastone of the abovementioned criteria (i), (ii) and (iii). In some suchembodiments, the therapeutically active agent meets at least two of theabovementioned criteria (i), (ii) and (iii).

Dihydroergotamine and fondaparinux are non-limiting examples ofnon-peptidic agents having a molecular weight of at least 0.5 kDa, whichare poorly absorbed upon oral administration.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent has a molecular weight of less than 0.5kDa, and meets at least one of the abovementioned criteria (i), (ii) and(iii). In some such embodiments, the therapeutically active agent meetsat least two of the abovementioned criteria (i), (ii) and (iii). In somesuch embodiments, the therapeutically active agent meets all three ofthe abovementioned criteria (i), (ii) and (iii).

In addition, ionic molecules tend to be poorly absorbed upon oraladministration, generally due to a considerably reduced ability to crosslipid membranes. Whether a molecule is ionic or non-ionic often dependson pH, which varies according to location in the gastrointestinal tract.In general, it is believed that the more a therapeutically active agentis in ionic form in the gastrointestinal tract, the more likely it is tobe poorly absorbed upon oral administration.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of7.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of6.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of5.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of4.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of3.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of2.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at a pH of1.0.

Examples of such agents include, without limitation, compoundscomprising at least one basic group (e.g., amine group) which ispositively charged at a pH of 7.0 (or less).

Herein, a compound is considered “ionic” when it comprises at least onefunctional group which is charged in at least 50% of the molecules in apopulation of molecules of the compound under designated conditions(e.g., in an aqueous solution at a designated pH value or range of pHvalues). The skilled person will be readily capable of determiningwhether a functional group is charged in at least 50% of the molecules,for example, by determining a pKa value associated with the functionalgroup. An ionic compound, as defined herein, may optionally have a netnegative charge, optionally a net positive charge, and optionally anequal number of negatively charged functional groups and positivelyfunctional groups, resulting in no net charge.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic in an aqueous solution at all pHvalues within a range of from 5.0 to 7.0. In some embodiments, thetherapeutically active agent is ionic in an aqueous solution at all pHvalues within a range of from 5.0 to 8.0. In some embodiments, thetherapeutically active agent is ionic in an aqueous solution at all pHvalues within a range of from 4.0 to 9.0. In some embodiments, thetherapeutically active agent is ionic in an aqueous solution at all pHvalues within a range of from 3.0 to 10.0. In some embodiments, thetherapeutically active agent is ionic in an aqueous solution at all pHvalues within a range of from 2.0 to 11.0.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is ionic at a pH value and/or rangeaccording to any one of the abovementioned embodiments, and further hasa molecular weight of at least 0.5 kDa, in accordance with any one ofthe embodiments described herein relating to a molecular weight of atleast 0.5 kDa. In some embodiments of any one of the embodimentsdescribed herein, the therapeutically active agent is ionic at a pHvalue and/or range according to any one of the abovementionedembodiments, and further has a molecular weight of less than 0.5 kDa.

Examples of ionic therapeutically active agents which tend to have amolecular weight of less than 0.5 kDa, and which tend to exhibit poorabsorption upon oral administration, include, without limitation,bisphosphonates (e.g., for use in treating osteoporosis and relatedconditions) such as alendronate, clodronate, etidronate, ibandronate,neridronate, olpadronate, pamidronate, risedronate, tiludronate andzoledronate; and cromolyn (e.g., cromolyn sodium).

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is a Class III agent according to theBiopharmaceutics Classification System (BCS), as provided by the U.S.FDA, that is, the therapeutically active agent is characterized by lowpermeability and high solubility.

In the context of the BCS, the phrase “low permeability” refers hereinand in the art to absorption of less than 90% of a given agent upon oraladministration in humans (in the absence of SNAC), as determined bymass-balance determination and/or in comparison to an intravenous dose.

In some embodiments, absorption of a Class III therapeutically activeagent is less than 50% upon oral administration (in the absence ofSNAC). In some embodiments, absorption is less than 20% upon oraladministration (in the absence of SNAC). In some embodiments, absorptionis less than 10% upon oral administration (in the absence of SNAC). Insome embodiments, absorption is less than 5% upon oral administration(in the absence of SNAC). In some embodiments, absorption is less than2% upon oral administration (in the absence of SNAC). In someembodiments, absorption is less than 1% upon oral administration (in theabsence of SNAC).

In the context of the BCS, the phrase “high solubility” refers hereinand in the art to an amount of therapeutically active agent in anadministered dose being soluble in 250 ml or less of water over a pHrange of 1 to 7.5.

In some embodiments of any one of the embodiments described herein, abioavailability of the therapeutically active agent upon oraladministration of the composition is in a range of from 0.05 to 50%. Insome embodiments, the bioavailability is in a range of from 0.1 to 15%.In some embodiments, the bioavailability is in a range of from 0.2 to5%. In some embodiments, the bioavailability is in a range of from 0.5to 3%.

Without being bound by any particular theory, it is believed that SNACenhances the bioavailability of the therapeutically active agentconsiderably. It is further believed that enhancing absorption for acontrolled period of time, in accordance with some of the embodimentsdescribed herein, results in a somewhat lower bioavailability than thatwhich occurs upon enhancement of absorption for a time period which isnot controlled.

In some embodiments of any one of the embodiments described herein, abioavailability of the therapeutically active agent upon oraladministration of the composition is at least 50% higher than (150% ofthe level of) a bioavailability of the therapeutically active agent uponoral administration of an equivalent composition which lacks SNAC (e.g.,being identical in all aspects except for the absence of SNAC). In someembodiments, the bioavailability is at least twice (200% of the levelof) the bioavailability upon oral administration of an equivalentcomposition which lacks SNAC. In some embodiments, the bioavailabilityis at least four-fold (400% of the level of) the bioavailability uponoral administration of an equivalent composition which lacks SNAC. Insome embodiments, the bioavailability is at least ten-fold (1000% of thelevel of) the bioavailability upon oral administration of an equivalentcomposition which lacks SNAC. In some embodiments, the bioavailabilityis at least twenty-fold (2000% of the level of) the bioavailability uponoral administration of an equivalent composition which lacks SNAC. Insome embodiments, the bioavailability is at least fifty-fold (5000% ofthe level of) the bioavailability upon oral administration of anequivalent composition which lacks SNAC.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is a natural or synthetic hormone and/orcytokine which is regulated in vivo by a negative feedback loop, suchthat continuous exposure to administered hormone may result in the bodyproducing less of a hormone and/or cytokine similar or identical to theadministered hormone and/or cytokine, thereby at least partiallyneutralizing a therapeutic effect of administering exogenous hormoneand/or cytokine. In some embodiments, the negative feedback isassociated with adverse effects of administration of exogenous hormoneand/or cytokine per se (e.g., by parenteral administration).

Without being bound by any particular theory, it is believed that apharmacokinetic profile of compositions described herein can decreaseand even eliminate effects of negative feedback, by allowing levels ofthe therapeutically active agent to return to normal levels before asubstantial (e.g., long-term) negative feedback effect is induced.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is a modulator of blood glucose levels.

In some embodiments, the therapeutically active agent reduces bloodglucose levels, and may be used, for example, to treat hyperglycemia.Insulin and GLP-1 are non-limiting examples of such an agent.

In some embodiments, the therapeutically active agent increases bloodglucose levels, and may be used, for example, to treat hypoglycemia.Glucagon is a non-limiting example of such an agent.

Without being bound by any particular theory, it is believed that apharmacokinetic profile of compositions described herein is particularlyuseful for treating acute hyperglycemia and/or hypoglycemia, whiledecreasing and even eliminating a risk of overshoot, whereby treatinghyperglycemia results in hypoglycemia, or treating hypoglycemia resultsin hyperglycemia.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is an agent characterized in that acuteexposure to the agent results in a substantially different biologicaleffect than does chronic exposure.

Herein, the phrase “substantially different biological effect” meansthat at least a portion of the effects differ in type rather than inmagnitude. In some embodiments, opposite effects are exhibited by acutevs. chronic exposure.

Parathyroid hormone is an example of an agent characterized in thatacute exposure to the agent results in a substantially differentbiological effect than does chronic exposure, as acute exposure causes anet enhancement of bone growth, whereas chronic exposure causes a netenhancement of bone resorption (effectively the opposite of enhancingbone growth). Enhancement of bone growth may optionally be used fortreating, for example, osteoporosis.

Without being bound by any particular theory, it is believed that apharmacokinetic profile of compositions described herein can provideparticularly pronounced and/or consistent effects associated with acuteexposure to an agent, for example, pronounced and consistent enhancementof bone growth by parathyroid hormone and similar agents.

In some embodiments of any one of the embodiments described herein, thetherapeutically active agent is oxytocin or an analog thereof, and thecomposition is for inducing labor.

Without being bound by any particular theory, it is believed that apharmacokinetic profile of compositions described herein can allow forinduction of labor by a brief presence of oxytocin in the blood, whiledecreasing a risk of adverse effects of oxytocin (e.g., more painfullabor) by decreasing the time period during which the administeredoxytocin is in the blood.

In some embodiments of any one of the embodiments described herein, thecomposition is for use in the treatment of a condition treatable by oraladministration of the therapeutically active agent (e.g., a conditiondescribed herein).

According to another aspect of embodiments of the invention, there isprovided a use of a composition according to any one of the embodimentsdescribed herein in the preparation of a medicament for use in thetreatment of a condition treatable by oral administration of thetherapeutically active agent (e.g., a condition described herein).

According to another aspect of embodiments of the invention, there isprovided a method of treating a condition treatable by oraladministration of a therapeutically active agent in a subject in needthereof (e.g., a condition and therapeutically active agent describedherein), the method comprising orally administering to the subject acomposition which comprises the therapeutically active agent, accordingto any one of the embodiments described herein.

Conditions treatable by the compositions and methods as described hereindepend on the therapeutically active agents included in the composition,and should be recognized by persons skilled in the art.

For example, when the therapeutically active agent is insulin or GLP-1,the condition treatable by the compositions and methods described hereincan be hyperglycemia and/or a condition associated with hyperglycemia,for example, diabetes.

When the therapeutically active agent is glucagon, the conditiontreatable by the compositions and methods described herein can behypoglycemia and/or a condition associated with hypoglycemia, forexample, hyperinsulinemia, hormone deficiency and/or infection, toxicityand/or organ failure associated with hypoglycemia.

When the therapeutically active agent is PTH or a fragment thereof, thecondition treatable by the compositions and methods described herein canbe osteoporosis, a bone fracture, a bone defect and/or a medicalcondition associated with a bone fracture and/or bone defect, forexample, bone resorption (e.g., resorption of alveolar bone associatedwith a missing tooth, bone resorption associated with inflammation)and/or a presence of an implant in a bone.

As used herein, the term “treatable” refers to an expected ability of anagent to treat a condition (as defined herein), based on knowledgeavailable to a person of ordinary skill in the relevant medical art, forexample, knowledge that the agent has been used to treat a conditionand/or that the agent exhibits a biological effect which is beneficialfor treating the condition.

In some embodiments of any one of the embodiments of the various aspectsdescribed herein, the treatment or method described herein ischaracterized in that it comprises enhancing absorption of thetherapeutically active agent for a controlled period of time.

In some embodiments of any one of the embodiments described herein,enhancing absorption is for no more than 60 minutes after oraladministration. In some embodiments, enhancing absorption is for no morethan 50 minutes. In some embodiments, enhancing absorption is for nomore than 40 minutes. In some embodiments, enhancing absorption is forno more than 30 minutes. In some embodiments, enhancing absorption isfor no more than 20 minutes. In some embodiments, enhancing absorptionis for no more than 15 minutes. In some embodiments, enhancingabsorption is for no more than 10 minutes.

In some embodiments of any one of the embodiments described herein, theenhanced absorption for a controlled period of time is such that a ratioof AUC to Cmax (as defined herein) is 60 minutes or lower. In someembodiments, the ratio of AUC to Cmax is 50 minutes or lower. In someembodiments, the ratio of AUC to Cmax is 40 minutes or lower. In someembodiments, the ratio of AUC to Cmax is 30 minutes or lower. In someembodiments, the ratio of AUC to Cmax is 20 minutes or lower. In someembodiments, the ratio of AUC to Cmax is 15 minutes or lower. In someembodiments, the ratio of AUC to Cmax is 10 minutes or lower.

In some embodiments of any one of the embodiments described herein, thecontrolled period of time is such that a Tmax upon oral administrationis no more than 60 minutes. In some embodiments, the Tmax is no morethan 50 minutes. In some embodiments, the Tmax is no more than 40minutes. In some embodiments, the Tmax is no more than 30 minutes. Insome embodiments, the Tmax is no more than 25 minutes. In someembodiments, the Tmax is no more than 20 minutes. In some embodiments,the Tmax is no more than 15 minutes. In some embodiments, the Tmax is nomore than 10 minutes. In some embodiments, the Tmax is no more than 5minutes.

Any formulation which provides desired pharmacokinetic parametersaccording to any of the respective embodiments described herein issuitable for use according to embodiments of the invention in thetreatment of the indicated medical conditions, and is encompassed by theterms “pharmaceutical composition” and “medicament” recited herein.

Such formulations may include ingredients or combinations of ingredientsknown to a person skilled in the art as providing the desiredpharmacokinetic parameters according to any of the respectiveembodiments described herein.

Any of the compositions and unit dosage forms described herein mayoptionally consist essentially of the ingredients described hereinabove(e.g., a therapeutically active agent, SNAC, and optionally at least oneprotease inhibitor), or alternatively, the composition further comprisessuitable pharmaceutically acceptable carriers or excipients.

Hereinafter, the phrases “physiologically acceptable carrier” and“pharmaceutically acceptable carrier”, which may be interchangeablyused, refer to a carrier or a diluent that does not cause significantirritation to an organism and does not abrogate the biological activityand properties of the administered compound. An adjuvant is includedunder these phrases.

Herein the term “excipient” refers to an inert substance added to apharmaceutical composition to further facilitate administration of anactive ingredient. Examples, without limitation, of excipients includecalcium carbonate, calcium phosphate, various sugars and types ofstarch, cellulose derivatives, gelatin, vegetable oils and polyethyleneglycols.

The term “unit dosage form”, as used herein, describes physicallydiscrete units, each unit containing a predetermined quantity of one ormore active ingredient(s) calculated to produce the desired therapeuticeffect, in association with at least one pharmaceutically acceptablecarrier, diluent, excipient, or combination thereof.

In some embodiments of any one of the embodiments described herein, thecomposition is formulated as a solid composition. In some embodiments,the composition is formulated as a tablet.

In some embodiments of any one of the embodiments described herein, thecomposition consists primarily of the combination of therapeuticallyactive agent, SNAC, and optional at least one protease inhibitordescribed herein, that is, at least 50 weight percents of thecomposition consists of ingredients selected from the group consistingof a therapeutically active agent, SNAC and (optional) at least oneprotease inhibitor. In some embodiments, at least 60 weight percents ofthe composition consists of a therapeutically active agent, SNAC and(optional) at least one protease inhibitor. In some embodiments, atleast 70 weight percents of the composition consists of atherapeutically active agent, SNAC and (optional) at least one proteaseinhibitor. In some embodiments, at least 80 weight percents of thecomposition consists of a therapeutically active agent, SNAC and(optional) at least one protease inhibitor. In some embodiments, atleast 90 weight percents of the composition consists of atherapeutically active agent, SNAC and (optional) at least one proteaseinhibitor. In some embodiments, at least 95 weight percents of thecomposition consists of a therapeutically active agent, SNAC and(optional) at least one protease inhibitor. In some embodiments, atleast 98 weight percents of the composition consists of atherapeutically active agent, SNAC and (optional) at least one proteaseinhibitor. In some embodiments, the composition is formulated as atablet.

In some embodiments of any one of the embodiments described herein, atleast 50 weight percents of the composition consists of SNAC. In someembodiments, at least 60 weight percents of composition consists ofSNAC. In some embodiments, at least 70 weight percents of compositionconsists of SNAC. In some embodiments, at least 80 weight percents ofcomposition consists of SNAC. In some embodiments, at least 90 weightpercents of composition consists of SNAC.

Without being bound by any particular theory, it is believed thatcompositions having a large proportion of SNAC, which is a salt, tend tobe readily soluble in aqueous solution, including in gastric fluid, asis desirable according to some embodiments of the invention.

Techniques for formulation and administration of drugs may be found in“Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa.,latest edition, which is incorporated herein by reference.

Pharmaceutical compositions of some embodiments of the invention may bemanufactured by processes well known in the art, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with some embodimentsof the invention thus may be formulated in conventional manner using oneor more physiologically acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active ingredients intopreparations which, can be used pharmaceutically.

The pharmaceutical composition can be formulated readily by combiningthe active compounds with pharmaceutically acceptable carriers wellknown in the art as being suitable for oral administration. Suchcarriers optionally facilitate formulation of the pharmaceuticalcomposition as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions, and the like, for oral ingestion by a patient.Pharmacological preparations for oral use can be made using a solidexcipient, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries if desired, toobtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; and/orphysiologically acceptable polymers such as polyvinylpyrrolidone (PVP).If desired, disintegrating agents may be added, such as cross-linkedpolyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such assodium alginate; and/or lubricants such as talc or magnesium stearate.

In some embodiments of any one of the embodiments described herein, thecomposition (e.g., formulated as a tablet) further comprises alubricant. In some embodiments, the lubricant is included in aconcentration of 5 weight percents or less, optionally 2 weight percentsor less, and optionally about 1 weight percent. In some embodiments, thecomposition (e.g., formulated as a tablet) consists essentially of thetherapeutically active agent (as described herein), SNAC, lubricant andoptionally at least one protease inhibitor (as described herein). Insome embodiments, the lubricant is magnesium stearate.

Dragee cores are optionally provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, titanium dioxide, lacquer solutions and suitableorganic solvents or solvent mixtures. Dyestuffs or pigments may be addedto the tablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical compositions which can be used orally include push-fitcapsules made of gelatin as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive ingredients may be dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers may be added.

Pharmaceutical compositions suitable for use in context of someembodiments of the invention include compositions wherein thetherapeutically active agent is contained in an amount effective toachieve the intended purpose. More specifically, the compositionpreferably comprises a therapeutically effective amount oftherapeutically active agent, that is, an amount of therapeuticallyactive agent effective to prevent, alleviate or ameliorate symptoms of adisorder or prolong the survival of the subject being treated.Furthermore, an amount of SNAC is preferably effective for enhancingabsorption of the therapeutically active agent (e.g., in a mannerdescribed herein); and an amount of protease inhibitor is preferablyeffective for inhibiting degradation of the therapeutically active agent(e.g., a polypeptide agent) by a protease.

Determination of a therapeutically effective amount is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein.

For any preparation used in the methods of the invention, thetherapeutically effective amount or dose can be estimated initially fromin vitro and cell culture assays. For example, a dose can be formulatedin animal models to achieve a desired concentration or titer. Suchinformation can be used to more accurately determine useful doses inhumans.

Toxicity and therapeutic efficacy of the therapeutically active agentdescribed herein can be determined by standard pharmaceutical proceduresin vitro, in cell cultures or experimental animals. The data obtainedfrom these in vitro and cell culture assays and animal studies can beused in formulating a range of dosage for use in human. The dosage mayvary depending upon the dosage form employed and the route ofadministration utilized. The exact formulation and dosage can be chosenby the individual physician in view of the patient's condition. (Seee.g., Fingl, et al., 1975, in “The Pharmacological Basis ofTherapeutics”, Ch. 1 p. 1).

Dosage amount and interval may be adjusted individually to providelevels (e.g., plasma levels) of the therapeutically active agentsufficient to induce or suppress a biological effect (minimal effectiveconcentration, MEC). The MEC will vary for each preparation, but can beestimated from in vitro data. Dosages necessary to achieve the MEC willdepend on individual characteristics. Detection assays can be used todetermine plasma concentrations.

Depending on the severity and responsiveness of the condition to betreated, dosing can be of a single or a plurality of administrations,with course of treatment lasting from several hours to several weeks oruntil cure is effected or diminution of the disease state is achieved.

The amount of a composition to be administered will, of course, bedependent on the subject being treated, the severity of the affliction,the manner of administration, the judgment of the prescribing physician,etc.

Compositions of some embodiments of the invention may, if desired, bepresented in a pack or dispenser device, such as an FDA approved kit,which may contain one or more unit dosage forms containing the activeingredient. The pack may, for example, comprise metal or plastic foil,such as a blister pack. The pack or dispenser device may be accompaniedby instructions for administration. The pack or dispenser may also beaccommodated by a notice associated with the container in a formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals, which notice is reflective of approval by theagency of the form of the compositions or human or veterinaryadministration. Such notice, for example, may be of labeling approved bythe U.S. Food and Drug Administration for prescription drugs or of anapproved product insert. Compositions comprising a preparation of theinvention may also be prepared (e.g., as described herein), placed in anappropriate container, and labeled for treatment of an indicatedcondition, as is further detailed herein.

Herein, the term “polypeptide” refers to a polymer comprising at least 4amino acid residues linked by peptide bonds or analogs thereof (asdescribed herein below), and optionally only by peptide bonds per se. Insome embodiments, the polypeptide comprises at least 10 amino acidresidues or analogs thereof. In some embodiments, the polypeptidecomprises at least 20 amino acid residues or analogs thereof. In someembodiments, the polypeptide comprises at least 30 amino acid residuesor analogs thereof. In some embodiments, the polypeptide comprises atleast 50 amino acid residues or analogs thereof. The term “polypeptide”encompasses native polypeptides (e.g., degradation products,synthetically synthesized polypeptides and/or recombinant polypeptides),including, without limitation, native proteins, fragments of nativeproteins and homologs of native proteins and/or fragments thereof; aswell as peptidomimetics (typically, synthetically synthesizedpolypeptides) and peptoids and semipeptoids which are polypeptideanalogs, which may have, for example, modifications rendering thepolypeptides more stable while in a body or more capable of penetratinginto cells. Such modifications include, but are not limited to Nterminus modification, C terminus modification, peptide bondmodification, backbone modifications, and residue modification. Methodsfor preparing peptidomimetic compounds are well known in the art and arespecified, for example, in Quantitative Drug Design, C. A. Ramsden Gd.,Chapter 17.2, F. Choplin Pergamon Press (1992), which is incorporated byreference as if fully set forth herein. Further details in this respectare provided herein below.

Peptide bonds (—CO—NH—) within the polypeptide may be substituted, forexample, by N-methylated amide bonds (—N(CH₃)—CO—), ester bonds(—C(═O)—O—), ketomethylene bonds (—CO—CH₂—), sulfinylmethylene bonds(—S(═O)—CH₂—), α-aza bonds (—NH—N(R)—CO—), wherein R is any alkyl (e.g.,methyl), amine bonds (—CH₂—NH—), sulfide bonds (—CH₂—S—), ethylene bonds(—CH₂—CH₂—), hydroxyethylene bonds (—CH(OH)—CH₂—), thioamide bonds(—CS—NH—), olefinic double bonds (—CH═CH—), fluorinated olefinic doublebonds (—CF═CH—), retro amide bonds (—NH—CO—), peptide derivatives(—N(R)—CH2-CO—), wherein R is the “normal” side chain, naturally presenton the carbon atom.

These modifications can occur at any of the bonds along the polypeptidechain and even at several (2-3) bonds at the same time.

Natural aromatic amino acids, Trp, Tyr and Phe, may be substituted bynon-natural aromatic amino acids such as1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), naphthylalanine,ring-methylated derivatives of Phe, halogenated derivatives of Phe orO-methyl-Tyr.

The polypeptides of some embodiments of the invention (e.g., atherapeutically active agent and/or a protease inhibitor describedherein) may also include one or more modified amino acids or one or morenon-amino acid monomers (e.g. fatty acids, complex carbohydrates etc).

The term “amino acid” or “amino acids” is understood to include the 20naturally occurring amino acids; those amino acids often modifiedpost-translationally in vivo, including, for example, hydroxyproline,phosphoserine and phosphothreonine; and other unusual amino acidsincluding, but not limited to, 2-aminoadipic acid, hydroxylysine,isodesmosine, nor-valine, nor-leucine and ornithine. Furthermore, theterm “amino acid” includes both D- and L-amino acids.

Tables 1 and 2 below list naturally occurring amino acids (Table 1), andnon-conventional or modified amino acids (e.g., synthetic, Table 2)which can be used with some embodiments of the invention.

TABLE 1 Three-Letter One-letter Amino Acid Abbreviation Symbol AlanineAla A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Cysteine Cys CGlutamine Gln Q Glutamic Acid Glu E Glycine Gly G Histidine His HIsoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met MPhenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr TTryptophan Trp W Tyrosine Tyr Y Valine Val V Any amino acid as above XaaX

TABLE 2 Non-conventional amino Non-conventional amino acid Code acidCode ornithine Orn hydroxyproline Hyp α-aminobutyric acid Abuaminonorbornyl- Norb carboxylate D-alanine Dala aminocyclopropane- Cprocarboxylate D-arginine Darg N-(3- Narg guanidinopropyl)glycineD-asparagine Dasn N-(carbamylmethyl)glycine Nasn D-aspartic acid DaspN-(carboxymethyl)glycine Nasp D-cysteine Dcys N-(thiomethyl)glycine NcysD-glutamine Dgln N-(2-carbamylethyl)glycine Ngln D-glutamic acid DgluN-(2-carboxyethyl)glycine Nglu D-histidine DhisN-(imidazolylethyl)glycine Nhis D-isoleucine DileN-(1-methylpropyl)glycine Nile D-leucine Dleu N-(2-methylpropyl)glycineNleu D-lysine Dlys N-(4-aminobutyl)glycine Nlys D-methionine DmetN-(2-methylthioethyl)glycine Nmet D-ornithine DornN-(3-aminopropyl)glycine Norn D-phenylalanine Dphe N-benzylglycine NpheD-proline Dpro N-(hydroxymethyl)glycine Nser D-serine DserN-(1-hydroxyethyl)glycine Nthr D-threonine Dthr N-(3-indolylethyl)glycine Nhtrp D-tryptophan Dtrp N-(p-hydroxyphenyl)glycine NtyrD-tyrosine Dtyr N-(1-methylethyl)glycine Nval D-valine DvalN-methylglycine Nmgly D-N-methylalanine Dnmala L-N-methylalanine NmalaD-N-methylarginine Dnmarg L-N-methylarginine Nmarg D-N-methylasparagineDnmasn L-N-methylasparagine Nmasn D-N-methylasparatate DnmaspL-N-methylaspartic acid Nmasp D-N-methylcysteine DnmcysL-N-methylcysteine Nmcys D-N-methylglutamine Dnmgln L-N-methylglutamineNmgln D-N-methylglutamate Dnmglu L-N-methylglutamic acid NmgluD-N-methylhistidine Dnmhis L-N-methylhistidine NmhisD-N-methylisoleucine Dnmile L-N-methylisolleucine NmileD-N-methylleucine Dnmleu L-N-methylleucine Nmleu D-N-methyllysine DnmlysL-N-methyllysine Nmlys D-N-methylmethionine Dnmmet L-N-methylmethionineNmmet D-N-methylornithine Dnmorn L-N-methylornithine NmornD-N-methylphenylalanine Dnmphe L-N-methylphenylalanine NmpheD-N-methylproline Dnmpro L-N-methylproline Nmpro D-N-methylserine DnmserL-N-methylserine Nmser D-N-methylthreonine Dnmthr L-N-methylthreonineNmthr D-N-methyltryptophan Dnmtrp L-N-methyltryptophan NmtrpD-N-methyltyrosine Dnmtyr L-N-methyltyrosine Nmtyr D-N-methylvalineDnmval L-N-methylvaline Nmval L-norleucine Nle L-N-methylnorleucineNmnle L-norvaline Nva L-N-methylnorvaline Nmnva L-ethylglycine EtgL-N-methyl-ethylglycine Nmetg L-t-butylglycine TbugL-N-methyl-t-butylglycine Nmtbug L-homophenylalanine Hphe L-N-methyl-Nmhphe homophenylalanine α-naphthylalanine AnapN-methyl-α-naphthylalanine Nmanap penicillamine PenN-methylpenicillamine Nmpen γ-aminobutyric acid GabuN-methyl-γ-aminobutyrate Nmgabu cyclohexylalanine ChexaN-methyl-cyclohexylalanine Nmchexa cyclopentylalanine CpenN-methyl-cyclopentylalanine Nmcpen α-amino-α-methylbutyrate AabuN-methyl-α-amino-α- Nmaabu methylbutyrate α-aminoisobutyric acid AibN-methyl-α- Nmaib aminoisobutyrate D-α-methylarginine DmargL-α-methylarginine Marg D-α-methylasparagine Dmasn L-α-methylasparagineMasn D-α-methylaspartate Dmasp L-α-methylaspartate MaspD-α-methylcysteine Dmcys L-α-methylcysteine Mcys D-α-methylglutamineDmgln L-α-methylglutamine Mgln D-α-methyl glutamic acid DmgluL-α-methylglutamate Mglu D-α-methylhistidine Dmhis L-α-methylhistidineMhis D-α-methylisoleucine Dmile L-α-methylisoleucine MileD-α-methylleucine Dmleu L-α-methylleucine Mleu D-α-methyllysine DmlysL-α-methyllysine Mlys D-α-methylmethionine Dmmet L-α-methylmethionineMmet D-α-methylornithine Dmorn L-α-methylornithine MornD-α-methylphenylalanine Dmphe L-α-methylphenylalanine MpheD-α-methylproline Dmpro L-α-methylproline Mpro D-α-methylserine DmserL-α-methylserine Mser D-α-methylthreonine Dmthr L-α-methylthreonine MthrD-α-methyltryptophan Dmtrp L-α-methyltryptophan Mtrp D-α-methyltyrosineDmtyr L-α-methyltyrosine Mtyr D-α-methylvaline Dmval L-α-methylvalineMval N-cyclobutylglycine Ncbut L-α-methylnorvaline MnvaN-cycloheptylglycine Nchep L-α-methylethylglycine MetgN-cyclohexylglycine Nchex L-α-methyl-t-butylglycine MtbugN-cyclodecylglycine Ncdec L-α-methyl- Mhphe homophenylalanineN-cyclododecylglycine Ncdod α-methyl-α-naphthylalanine ManapN-cyclooctylglycine Ncoct α-methylpenicillamine MpenN-cyclopropylglycine Ncpro α-methyl-γ-aminobutyrate MgabuN-cycloundecylglycine Ncund α-methyl-cyclohexylalanine MchexaN-(2-aminoethyl)glycine Naeg α-methyl-cyclopentylalanine Mcpen N-(2,2-Nbhm N-(N-(2,2-diphenylethyl) Nnbhm diphenylethyl)glycinecarbamylmethyl-glycine N-(3,3- Nbhe N-(N-(3,3-diphenylpropyl) Nnbhediphenylpropyl)glycine carbamylmethyl-glycine 1-carboxy-1-(2,2-diphenylNmbc 1,2,3,4- Tic ethylamino)cyclopropane tetrahydroisoquinoline-3-carboxylic acid phosphoserine pSer phosphothreonine pThr phosphotyrosinepTyr O-methyl-tyrosine 2-aminoadipic acid hydroxylysine

The polypeptides of some embodiments of the invention (e.g., atherapeutically active agent and/or a protease inhibitor describedherein) are preferably utilized in a linear form, although it will beappreciated that in cases where cyclicization does not severelyinterfere with polypeptide characteristics, cyclic forms of thepolypeptide can also be utilized.

In some embodiments of any one of the embodiments described herein, thepolypeptide is water-soluble.

Herein, the term “water-soluble” refers to a compound having asolubility of at least 1 gram per liter in an aqueous solution at pH 7.

Water-soluble polypeptides preferably include one or more (non-naturalor natural) polar amino acids, including but not limited to serine andthreonine which are capable of increasing polypeptide water-solubilitydue to their hydroxyl-containing side chain. Optionally, a homolog of apolypeptide is selected so as to be more water-soluble than the parentpolypeptide, for example, by replacing one or more amino acids in thepolypeptide with polar amino acids.

The polypeptides of some embodiments of the invention (e.g., atherapeutically active agent and/or a protease inhibitor describedherein) may be synthesized by any techniques that are known to thoseskilled in the art of peptide synthesis. For solid phase peptidesynthesis, a summary of the many techniques may be found in J. M.Stewart and J. D. Young, Solid Phase Peptide Synthesis, W. H. FreemanCo. (San Francisco), 1963 and J. Meienhofer, Hormonal Proteins andPeptides, vol. 2, p. 46, Academic Press (New York), 1973. For classicalsolution synthesis see G. Schroder and K. Lupke, The Peptides, vol. 1,Academic Press (New York), 1965.

In general, these methods comprise the sequential addition of one ormore amino acids or suitably protected amino acids to a growingpolypeptide chain. Normally, either the amino or carboxyl group of thefirst amino acid is protected by a suitable protecting group. Theprotected or derivatized amino acid can then either be attached to aninert solid support or utilized in solution by adding the next aminoacid in the sequence having the complimentary (amino or carboxyl) groupsuitably protected, under conditions suitable for forming the amidelinkage. The protecting group is then removed from this newly addedamino acid residue and the next amino acid (suitably protected) is thenadded, and so forth. After all the desired amino acids have been linkedin the proper sequence, any remaining protecting groups (and any solidsupport) are removed sequentially or concurrently, to afford the finalpolypeptide compound. By simple modification of this general procedure,it is possible to add more than one amino acid at a time to a growingchain, for example, by coupling (under conditions which do not racemizechiral centers) a protected tripeptide with a properly protecteddipeptide to form, after deprotection, a pentapeptide and so forth.Further description of peptide synthesis is disclosed in U.S. Pat. No.6,472,505.

A preferred method of preparing the polypeptide compounds of someembodiments of the invention (e.g., a therapeutically active agentand/or a protease inhibitor described herein) involves solid phasepeptide synthesis.

Large scale polypeptide synthesis is described by Andersson et al.[Biopolymers 2000; 55:227-250].

Herein, a “homolog” of a given polypeptide refers to a polypeptide thatexhibits at least 80% homology, preferably at least 90% homology, andmore preferably at least 95% homology, and more preferably at least 98%homology to the given polypeptide. In some embodiments, a homolog of agiven polypeptide further shares a therapeutic activity with the givenpolypeptide. The percentage of homology refers to the percentage ofamino acid residues in a first polypeptide sequence which matches acorresponding residue of a second polypeptide sequence to which thefirst polypeptide is being compared. Generally, the polypeptides arealigned to give maximum homology. A variety of strategies are known inthe art for performing comparisons of amino acid or nucleotide sequencesin order to assess degrees of identity, including, for example, manualalignment, computer assisted sequence alignment and combinationsthereof. A number of algorithms (which are generally computerimplemented) for performing sequence alignment are widely available, orcan be produced by one of skill in the art. Representative algorithmsinclude, e.g., the local homology algorithm of Smith and Waterman (Adv.Appl. Math., 1981, 2: 482); the homology alignment algorithm ofNeedleman and Wunsch (J. Mol. Biol., 1970, 48: 443); the search forsimilarity method of Pearson and Lipman (Proc. Natl. Acad. Sci. (USA),1988, 85: 2444); and/or by computerized implementations of thesealgorithms (e.g., GAP, BESTFIT, FASTA, and TFASTA in the WisconsinGenetics Software Package Release 7.0, Genetics Computer Group, 575Science Dr., Madison, Wis.). Readily available computer programsincorporating such algorithms include, for example, BLASTN, BLASTP,Gapped BLAST, PILEUP, CLUSTALW etc. When utilizing BLAST and GappedBLAST programs, default parameters of the respective programs may beused. Alternatively, the practitioner may use non-default parametersdepending on his or her experimental and/or other requirements (see forexample, the Web site having URL www(dot)ncbi(dot)nlm(dot)nih(dot)gov).

It is expected that during the life of a patent maturing from thisapplication many relevant therapeutically active agents and manyrelevant treatments of conditions by therapeutically active agents willbe developed, and the scope of the phrases “therapeutically activeagent” and “condition treatable by . . . therapeutically active agent”are intended to include all such new technologies a priori.

As used herein the term “about” refers to ±10%.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean “including but not limited to”.

The term “consisting of” means “including and limited to”.

The term “consisting essentially of” means that the composition, methodor structure may include additional ingredients, steps and/or parts, butonly if the additional ingredients, steps and/or parts do not materiallyalter the basic and novel characteristics of the claimed composition,method or structure.

The word “exemplary” is used herein to mean “serving as an example,instance or illustration”. Any embodiment described as “exemplary” isnot necessarily to be construed as preferred or advantageous over otherembodiments and/or to exclude the incorporation of features from otherembodiments.

The word “optionally” is used herein to mean “is provided in someembodiments and not provided in other embodiments”. Any particularembodiment of the invention may include a plurality of “optional”features unless such features conflict.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a therapeutically active agent” may include a plurality ofcompounds, including mixtures thereof.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

As used herein the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

As used herein, the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a condition,substantially ameliorating clinical or aesthetical symptoms of acondition or substantially preventing the appearance of clinical oraesthetical symptoms of a condition.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Various embodiments and aspects of the present invention as delineatedhereinabove and as claimed in the claims section below find experimentalsupport in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with theabove descriptions illustrate some embodiments of the invention in anon-limiting fashion.

Materials

8-Aminocaprylic acid was obtained from Alfa-Aesar.

Magnesium stearate was obtained from Sigma-Aldrich.

O-acetylsalicyloyl chloride was obtained from Sigma-Aldrich.

Soybean trypsin inhibitor (SBTI) was obtained from Sigma-Aldrich.

Teriparatide was purchased from Bachem.

SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) was prepared byreacting O-acetylsalicyloyl chloride with 8-aminocaprylic acid.

Example 1

Pharmacokinetic Profile of Orally Administered Parathyroid Hormone (PTH)

Pharmacokinetic Study Design:

An open label comparative pharmacokinetic study was performed in healthyvolunteers over the course of 3 months. Each volunteer received—in eachof two visits—the same oral tablet containing 0.75 mg of teriparatide, arecombinant form of parathyroid hormone (1-34).

The formulation was composed of teriparatide (0.75 mg), SNAC (sodium8-N-(2-hydroxybenzoyl) aminocaprylate), soybean trypsin inhibitor (SBTI)and a small amount of magnesium stearate.

Tablets were administered in the morning after an 8-hour overnight fastand immediately followed by 150 ml of water. At each visit a standardmeal was provided 3 hours after drug administration. Patients did noteat or drink alcoholic or caffeinated beverages. There was a two weeksperiod between the visits.

To determine parathyroid hormone (1-34) (PTH(1-34)) concentrations,blood samples (4 ml each) were drawn via an indwelling catheter from theforearm vein at predetermined time points during each visit. The cannulawas flushed with 1.5 ml normal saline after each sampling. In addition,to avoid sample dilution, 1 ml of blood was drawn and discarded beforethe next sample. The blood samples were taken at following times:baseline (predose), 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 2 hours, 3hours, 4 hours and 5 hours post-administration. Each blood sample wascollected into a single tube containing EDTA (ethylenediaminetetraaceticacid) and placed on ice. Within 15 minutes of blood collection, sampleswere centrifuged for 10 minutes at 4° C. (2500 rotations per minute) andthe plasma was separated and divided into two or three aliquots. Eachaliquot was transferred into appropriately labeled polypropylene tubesand stored at approximately −20° C. pending analysis. PTH (1-34) levelswere measured using an IDS-iSYS automated assay for the measurement ofintact PTH (1-34) in human plasma or serum. The results of the assay donot include levels of PTH (1-84) such as endogenous PTH.

Results:

As shown in Table 3 below and in FIGS. 1A-1C, the pharmacokineticprofile of the administered parathyroid hormone (1-34) was characterizedby a sharp increase in plasma levels, followed by a rapid decrease, suchthat a peak concentration (Cmax) of parathyroid hormone (1-34) occurredwithin 20 minutes of administration. As further shown therein, the Cmaxwas relatively constant between different administrations in a givensubject. As further shown in FIGS. 1A-1C, parathyroid hormone (1-34)levels returned to baseline levels within 60 minutes of tabletadministration.

As further shown in FIGS. 1A-1C, particularly in FIGS. 1B and 1C, evenslight variations in Tmax (e.g., from 10 to 20 minutes) result indifferent pharmacokinetic curves having little overlap, because thepeaks in PTH plasma levels are so narrow.

TABLE 3 Pharmacokinetic data for three subjects following two oraladministrations of teriparatide Tmax Tmax Cmax Cmax after 1st after 2ndafter 1st after 2nd Sub- administration administration administrationadministration ject (minutes) (minutes) (picogram/ml) (picogram/ml) A 1520 195 283 B 10 20 124 116 C 10 20 35 36

This result indicates the importance of data from individualmeasurements, as opposed to averaged data from different measurements.Averaging values from different measurements, even differentmeasurements in a single subject, would result in a broader and lowercurve which does not accurately represent the rapidity of increase anddecrease in plasma levels.

Example 2

Phase I Clinical Trial of Orally Administered Parathyroid Hormone (PTH)

A Phase I clinical study of exemplary oral formulations comprisingteriparatide (parathyroid hormone (1-34)) was conducted at the HadassahClinical Research Center. 42 healthy volunteers were included throughoutthe study.

The formulation was composed of teriparatide (200, 400, 680, 1400 or1800μ.g), SNAC (sodium 8-N-(2-hydroxybenzoyl) aminocaprylate), soybeantrypsin inhibitor and magnesium stearate.

Tablets were administered in the morning after an 8-hour overnight fastand immediately followed by 150 ml of water. At each visit a standardmeal was provided 3 hours after drug administration. Patients did noteat or drink alcoholic or caffeinated beverages.

To determine parathyroid hormone concentrations, blood samples (4 mleach) were drawn via an indwelling catheter from the forearm vein atpredetermined time points. The cannula was flushed with 1.5 ml normalsaline after each sampling. In addition, to avoid sample dilution, 1 mlof blood was drawn and discarded before the next sample. The bloodsamples were taken at following times: baseline (predose), 15 minutes,30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes,2 hours, 3 hours, 4 hours and 5 hours post-administration. Each bloodsample was collected into a single tube containing EDTA(ethylenediaminetetraacetic acid) and placed on ice. Within 15 minutesof blood collection, samples were centrifuged for 10 minutes at 4° C.(2500 rotations per minute) and the plasma was separated and dividedinto two or three aliquots. Each aliquot was transferred intoappropriately labeled polypropylene tubes and stored at approximately−20° C. pending analysis. PTH (1-34) levels were measured using anIDS-iSYS automated assay for the measurement of intact PTH (1-34) inhuman plasma or serum.

Oral administration of teriparatide was performed as describedhereinabove at doses of 200, 400, 680, 1400 or 1800 μg. The Cmax of PTH(1-34) for each orally administered dose was compared with the Cmax ofPTH (1-34) for subcutaneous injection of 20 μg teriparatide.

As shown in FIG. 2, the Cmax of PTH (1-34) following oral administrationwas proportional to the dose, with oral administration of roughly 750 μgteriparatide providing a Cmax equivalent to that of subcutaneousadministration of 20 μg teriparatide.

As shown in FIG. 3, oral administration of 1800 μg teriparatide andsubcutaneous administration of 20 μg teriparatide were characterized bysimilar Cmax values, the primary difference in pharmacokinetic profilebeing that PTH levels declined considerably more rapidly following oraladministration than after subcutaneous administration. It is to beappreciated that a pharmacokinetic profile for an individualadministration is characterized by a narrower and higher curve than thecurve shown in FIG. 3, because averaging data from differentmeasurements results in a broader and lower curve, due to slightvariations in Tmax (as discussed in Example 1).

In addition, plasma levels of cAMP, a known marker of PTH activity, weredetermined in order to confirm biological activity of administered PTH.cAMP plasma levels were measured following oral administration of 680 μgteriparatide or subcutaneous injection of 20 μg teriparatide, asdescribed hereinabove.

As shown in FIG. 4, oral administration of 680 μg teriparatide andsubcutaneous administration of 20 μg teriparatide increased plasma cAMPlevels to a similar degree. This result confirms that the orallyadministered PTH exhibits biological activity.

These results indicate that oral administration of PTH results inbiologically active increases in PTH levels, and for a briefer period oftime than obtained by subcutaneous administration.

The brief period of increased PTH levels in the blood may beadvantageous for enhancing bone growth, as chronic exposure to PTH hasthe opposite effect (enhancement of bone resorption) than intermittentexposure to PTH.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting.

1. A pharmaceutical composition comprising a therapeutically activeagent, and SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate), thecomposition being formulated such that absorption of saidtherapeutically active agent following oral administration of thecomposition is characterized by an average ratio of AUC to Cmax which is60 minutes or lower and/or by an average Tmax which is 60 minutes orlower.
 2. The composition of claim 1, wherein said average ratio of AUCto Cmax is 30 minutes or lower.
 3. The composition of claim 1, whereinsaid average Tmax is 30 minutes or lower.
 4. A pharmaceuticalcomposition comprising a therapeutically active agent, and SNAC (sodium8-N-(2-hydroxybenzoyl)aminocaprylate), the composition being formulatedfor oral administration and being such that said SNAC is active inenhancing absorption of the therapeutically active agent for no morethan 60 minutes.
 5. (canceled)
 6. The composition of claim 1, furthercomprising at least one protease inhibitor.
 7. The composition of claim6, wherein said at least one protease inhibitor comprises at least onetrypsin inhibitor.
 8. The composition of claim 7, wherein said at leastone trypsin inhibitor is selected from the group consisting of lima beantrypsin inhibitor, aprotinin, soybean trypsin inhibitor and ovomucoidtrypsin inhibitor.
 9. The composition of claim 7, wherein said at leastone trypsin inhibitor comprises soybean trypsin inhibitor.
 10. Thecomposition of claim 1, further comprising a lubricant.
 11. Thecomposition of claim 10, wherein said lubricant is magnesium stearate.12. The composition of claim 1, being soluble in gastric fluid.
 13. Thecomposition of claim 12, wherein the composition dissolves in saidgastric fluid in no more than 60 minutes.
 14. The composition of claim1, being formulated as a tablet.
 15. The composition of claim 14,wherein at least 90 weight percents of said tablet consists ofingredients selected from the group consisting of said therapeuticallyactive agent, SNAC, and at least one protease inhibitor.
 16. Thecomposition of claim 1, wherein at least 50 weight percents of thecomposition consists of SNAC.
 17. The composition of claim 1, comprisingat least 50 mg of SNAC.
 18. The composition of claim 1, wherein abioavailability of said therapeutically active agent is in a range offrom 0.05 to 50%.
 19. (canceled)
 20. The composition of claim 1, whereinsaid therapeutically active agent has a molecular weight in a range of0.5 kDa to 100 kDa.
 21. The composition of claim 1, wherein saidtherapeutically active agent is a polypeptide.
 22. The composition ofclaim 21, wherein said polypeptide is selected from the group consistingof parathyroid hormone and a fragment thereof.
 23. The composition ofclaim 21, wherein said polypeptide comprises teriparatide.
 24. Thecomposition of claim 20, wherein an amount of said therapeuticallyactive agent is in a range of from 100 to 3000 μg. 25-31. (canceled) 32.A method of treating a condition treatable by oral administration of atherapeutically active agent in a subject in need thereof, the methodcomprising orally administering to the subject the composition ofclaim
 1. 33. The method of claim 32, comprising enhancing absorption ofsaid therapeutically active agent for a controlled period of time, suchthat an average ratio of AUC to Cmax is 60 minutes or lower and/or suchthat an average Tmax is 60 minutes or lower.
 34. (canceled)
 35. Themethod of claim 32, comprising enhancing absorption of saidtherapeutically active agent for no more than 60 minutes after said oraladministration. 36-37. (canceled)